Co-reporter:Daniel J. Shaw;Rachel E. Hill;Niall Simpson;Fouad S. Husseini;Kirsty Robb;Gregory M. Greetham;Michael Towrie;Anthony W. Parker;David Robinson;Paul A. Hoskisson;Neil T. Hunt
Chemical Science (2010-Present) 2017 vol. 8(Issue 12) pp:8384-8399
Publication Date(Web):2017/11/20
DOI:10.1039/C7SC03336B
Antimicrobial resistance represents a growing global health problem. The emergence of novel resistance mechanisms necessitates the development of alternative approaches to investigate the molecular fundamentals of resistance, leading ultimately to new strategies for counteracting them. To gain deeper insight into antibiotic–target interactions, the binding of the frontline anti-tuberculosis drug isoniazid (INH) to a target enzyme, InhA, from Mycobacterium tuberculosis was studied using ultrafast two-dimensional infrared (2D-IR) spectroscopy and molecular simulations. Comparing wild-type InhA with a series of single point mutations, it was found that binding of the INH–NAD inhibitor to susceptible forms of the enzyme increased the vibrational coupling between residues located in the Rossmann fold co-factor binding site of InhA and suppressed dynamic fluctuations of the enzyme structure. The effect correlated with biochemical assay data, being reduced in the INH-resistant S94A mutant and absent in the biochemically-inactive P193A control. Molecular dynamics simulations and calculations of inter–residue couplings indicate that the changes in coupling and dynamics are not localised to the co-factor binding site, but permeate much of the protein. We thus propose that the resistant S94A mutation circumvents subtle changes in global structural dynamics caused by INH upon binding to the wild-type enzyme that may impact upon the formation of important protein–protein complexes in the fatty acid synthase pathway of M. tuberculosis.
Co-reporter:Zhuo Li
Chemical Science (2010-Present) 2017 vol. 8(Issue 6) pp:4318-4333
Publication Date(Web):2017/05/30
DOI:10.1039/C7SC00586E
Vibrational structure in the near-UV circular dichroism (CD) spectra of proteins is an important source of information on protein conformation and can be exploited to study structure and folding. A fully quantitative theory of the relationship between protein conformation and optical spectroscopy would facilitate deeper interpretation of and insight into biophysical and simulation studies of protein dynamics and folding. We have developed new models of the aromatic side chain chromophores toluene, p-cresol and 3-methylindole, which incorporate ab initio calculations of the Franck–Condon effect into first principles calculations of CD using an exciton approach. The near-UV CD spectra of 40 proteins are calculated with the new parameter set and the correlation between the computed and the experimental intensity from 270 to 290 nm is much improved. The contribution of individual chromophores to the CD spectra has been calculated for several mutants and in many cases helps rationalize changes in their experimental spectra. Considering conformational flexibility by using families of NMR structures leads to further improvements for some proteins and illustrates an informative level of sensitivity to side chain conformation. In several cases, the near-UV CD calculations can distinguish the native protein structure from a set of computer-generated misfolded decoy structures.
Co-reporter:Sonia Aguado-Ullate, John A. Baker, Vanessa González-González, Christian Müller, Jonathan D. Hirst and Jorge J. Carbó
Catalysis Science & Technology 2014 vol. 4(Issue 4) pp:979-987
Publication Date(Web):07 Jan 2014
DOI:10.1039/C3CY00956D
The factors governing the activity in Rh-catalyzed hydroformylation were investigated using a set of computational tools. We performed DFT calculations on the phosphinine-modified Rh catalyst [HRh(CO)3(PC5H2R3)] and compared it to the phosphane-modified HRh(CO)3(PR3) and HRh(CO)2(PR3)2 complexes. The π-acceptor phosphinine ligand coordinates preferentially at the equatorial site of the pentacoordinated Rh complex with the heterocycle perpendicular to the equatorial plane, although the ligand freely rotates around the Rh–P bond. The overall energy barrier can be divided into the following contributions: alkene complex formation, alkene rotation and alkene insertion. In the absence of steric effects (model systems), the overall barrier correlates with the computed barrier for alkene rotation. This proves that π-acceptor ligands reduce back-donation to the alkene, leading to a lower rotational barrier and, consequently, to a higher activity. The Rh–P donor–acceptor interactions were quantified using a modified version of energy decomposition analysis (EDA). In Rh–phosphinine systems, the efficient directionality of the π-back-donation, rather than the overall acceptor ability, is responsible for the high catalytic activity. Introducing steric effects increases the energy required to coordinate the alkene, increasing the overall barrier. The factors governing the activity in Rh–monophosphane catalysts seem to be related to those derived for Rh–diphosphane during the development of a QSAR model (Catal. Sci. Technol. 2012, 2, 1694). To investigate whether the findings for mono- can be extrapolated to diphosphane ligands, we re-examined our previous QSAR model using the Topological Maximum Cross Correlation (TMACC) method based on easy-to-interpret 2D-descriptors. The TMACC descriptors highlight heteroatoms close to phosphorus as activity-increasing atoms, whereas highly substituted carbon atom groups are highlighted as activity-decreasing groups.
Co-reporter:Eleanor R. Turpin, Huey-Jen Fang, Neil R. Thomas, and Jonathan D. Hirst
Biochemistry 2013 Volume 52(Issue 27) pp:
Publication Date(Web):June 12, 2013
DOI:10.1021/bi400192w
The ileal lipid binding protein (ILBP or I-BABP) binds bile salts with positive cooperativity and has unusual site selectivity, whereby cholic acid binds preferentially in one site and chenodeoxycholic in another, despite both sites having an affinity for both ligands and the ligands only differing by a single hydroxyl group. Previous studies of the human variant have assumed that the ligand/protein binding ratio is 2:1, but we show, using electrospray ionization mass spectroscopy, that human ILBP binds bile acids with a 3:1 ratio, even at low protein and ligand concentrations. Docking calculations and molecular dynamics (MD) simulations identify an allosterically active binding site on the protein exterior that induces a change from a closed conformation to an open one, characterized by a movement of one of the α-helices by ∼10° with respect to the β-clam shell. Additional independent MD simulations of several hundred nanoseconds implicate the change between conformations in the mechanisms of both cooperativity and ligand site selectivity.
Co-reporter:Mengchen Pu, Juan P. Garrahan, Jonathan D. Hirst
Chemical Physics Letters 2011 Volume 515(4–6) pp:283-289
Publication Date(Web):27 October 2011
DOI:10.1016/j.cplett.2011.09.026
Abstract
The dynamics of the Phox and Bem1p (PB1) domain, which adopts an ubiquitin-like β-grasp fold, have been simulated using two implicit solvent models (GBSW and EEF1.1) and two force fields (CHARMM19 and 22). The protein undergoes a large re-orientation using EEF1.1 with the CHARMM19 force field. This computational model is often applied in folding simulations. However, the conformational dynamics generated using EEF1.1 with the CHARMM22 force field are similar to those in the GBSW simulations and do not show any large re-orientation. These findings underscore the care needed in the selection of, not only the implicit solvent model, but also an appropriate protein force field.
Co-reporter:David Robinson, Nicholas A. Besley, Paul O’Shea, and Jonathan D. Hirst
The Journal of Physical Chemistry B 2011 Volume 115(Issue 14) pp:4160-4167
Publication Date(Web):March 22, 2011
DOI:10.1021/jp1111372
We have investigated the effects of explicit molecular interactions and the membrane dipole potential on the absorption and emission spectra of a widely used fluorescent probe, di-8-ANEPPS, in a dipalmitoylphosphatidylcholine (DPPC) and a mixed DPPC/cholesterol membrane bilayer. Ground-state and excited-state geometries were calculated with the complete active space self-consistent field (CASSCF) method. Interactions with up to 260 atoms of the membrane bilayer were explicitly incorporated using a decoupled quantum mechanics/molecular mechanics (QM/MM) approach, utilizing recent advances in time-dependent density functional theory (TDDFT). We find that no specific molecular interactions affect the fluorescence of di-8-ANEPPS; rather, the magnitude of the membrane dipole potential is key to the shifts observed in both of the two lowest excited states.
Co-reporter:Marie-Pierre Gaigeot, Nicholas A. Besley, and Jonathan D. Hirst
The Journal of Physical Chemistry B 2011 Volume 115(Issue 18) pp:5526-5535
Publication Date(Web):February 23, 2011
DOI:10.1021/jp111140f
Density functional theory based molecular dynamics simulations are used to study the structure, infrared (IR) spectroscopy, circular dichroism (CD) spectroscopy, and coupling between the amide I vibrations of a bridged cyclic diamide in the gas phase and in aqueous solution. IR spectra computed via the dipole moment time correlation function show a large red-shift of 30 cm−1 in the amide I vibration in solution compared to the gas phase, and are in good agreement with experiment. Conformationally averaged CD spectra computed using the CIS(D) method are highly sensitive to the structures used, and structures sampled in the aqueous phase simulation are required to obtain qualitatively correct CD spectra. Analysis of the coupling between the amide I modes shows that in the aqueous phase there is an increased localization of the vibrations on the individual peptide groups and a reduction in the mode coupling parameter compared to the gas phase. Overall, the results illustrate the significance of incorporating molecular dynamics in the simulation of IR and CD spectra.
Co-reporter:Darius Abramavicius ; Jun Jiang ; Benjamin M. Bulheller ; Jonathan D. Hirst ;Shaul Mukamel
Journal of the American Chemical Society 2010 Volume 132(Issue 22) pp:7769-7775
Publication Date(Web):May 18, 2010
DOI:10.1021/ja101968g
Amide n−π* and π−π* excitations around 200 nm are prominent spectroscopic signatures of the protein backbone, which are routinely used in ultraviolet (UV) circular dichroism for structure characterization. Recently developed ultrafast laser sources may be used to extend these studies to two dimensions. We apply a new algorithm for modeling protein electronic transitions to simulate two-dimensional UV photon echo signals in this regime and to identify signatures of protein backbone secondary (and tertiary) structure. Simulated signals for a set of globular and fibrillar proteins and their specific regions reveal characteristic patterns of helical and sheet secondary structures. We investigate how these patterns vary and converge with the size of the structural motif. Specific chiral polarization configurations of the UV pulses are found to be sensitive to aspects of the protein structure. This information significantly augments that available from linear circular dichroism.
Co-reporter:Hainam Do, Richard J. Wheatley and Jonathan D. Hirst
Physical Chemistry Chemical Physics 2010 vol. 12(Issue 40) pp:13266-13272
Publication Date(Web):07 Sep 2010
DOI:10.1039/C0CP00620C
1-1-1-2-tetrafluoroethane (R134a) is one of the most commonly used refrigerants. Its thermophysical properties are important for evaluating the performance of refrigeration cycles. These can be obtained via computer simulation, with an insight into the microscopic structure of the liquid, which is not accessible to experiment. In this paper, vapour–liquid equilibrium properties of R134a and its liquid microscopic structure are investigated using coupled–decoupled configurational-bias Monte Carlo simulation in the Gibbs ensemble, with a recent potential [J. Phys. Chem. B 2009, 113, 178]. We find that the simulations agree well with the experimental data, except at the vicinity of the critical region. Liquid R134a packs like liquid argon, with a coordination number in the first solvation shell of 12 at 260 K. The nearest neighbours prefer to be localized in three different spaces around the central molecule, in such a manner that the dipole moments are in a parallel alignment. Analysis of the pair interaction energy shows clear association of R134a molecules, but no evidence for C–H⋯F type hydrogen bonding is found. The above findings should be of relevance to a broad range of fluoroalkanes.
Co-reporter:Eleanor R. Turpin, Boyan B. Bonev, and Jonathan D. Hirst
Biochemistry 2010 Volume 49(Issue 44) pp:
Publication Date(Web):September 30, 2010
DOI:10.1021/bi101214t
Nisin is a polymacrocyclic peptide antimicrobial with high activity against Gram-positive bacteria. Lanthionine and methyllanthionine bridges, closing the macrocycles, are stabilized by thioether bonds, formed between cysteines and dehydrated serine or threonine. The role of polypeptide backbone conformation in the formation of macrocycles A and B within cysteine mutants of nisin residues 1−12 is investigated here by molecular dynamics simulations. Enantiomeric combinational space of Cys3 and Cys7 and of Cys8 and Cys11 is examined for the preference of disulfide bond formation over helical turn formation within this region. A clear preference for spontaneous disulfide formation and closure of rings 3,7 and 8,11 is demonstrated for the d-Cys3, d-Cys7, l-Cys8, l-Cys11 nisin homologue, while interlinked rings A and B are obtained through disulfide bridges between l-Cys3 and d-Cys8 and between d-Cys7 and d-Cys11. This study offers a simple designer approach to solid phase synthesis of macrocyclic peptides and lantibiotic analogues.
Co-reporter:Jonathan D. Hirst, Jeffry D. Madura
Journal of Molecular Graphics and Modelling 2010 Volume 29(Issue 2) pp:115
Publication Date(Web):September 2010
DOI:10.1016/j.jmgm.2010.07.001
Co-reporter:Jonathan D. Hirst, Jeffry D. Madura
Journal of Molecular Graphics and Modelling 2010 Volume 29(Issue 1) pp:1
Publication Date(Web):24 August 2010
DOI:10.1016/j.jmgm.2010.06.005
Co-reporter:Abrar Hussain;James L. Melville
Journal of Computer-Aided Molecular Design 2010 Volume 24( Issue 1) pp:1-15
Publication Date(Web):2010 January
DOI:10.1007/s10822-009-9307-y
Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide ‘tail’ to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q2 value of 0.85 and a r2 of 0.94. Results from the docking simulations and the interpretation from QSAR “coeff*stdev” contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues.
Co-reporter:Benjamin M. Bulheller ; Alison Rodger ; Matthew R. Hicks ; Timothy R. Dafforn ; Louise C. Serpell ; Karen E. Marshall ; Elizabeth H. C. Bromley ; Patrick J. S. King ; Kevin J. Channon ; Derek N. Woolfson
Journal of the American Chemical Society 2009 Volume 131(Issue 37) pp:13305-13314
Publication Date(Web):August 28, 2009
DOI:10.1021/ja902662e
Flow linear dichroism (LD) spectroscopy provides information on the orientation of molecules in solution and hence on the relative orientation of parts of molecules. Long molecules such as fibrous proteins can be aligned in Couette flow cells and characterized using LD. We have measured using Couette flow and calculated from first principles the LD of proteins representing prototypical secondary structure classes: a self-assembling fiber and tropomyosin (all-α-helical), FtsZ (an αβ protein), an amyloid fibril (β-sheet), and collagen [poly(proline)II helices]. The combination of calculation and experiment allows elucidation of the protein orientation in the Couette flow and the orientation of chromophores within the protein fibers.
Co-reporter:Benjamin M. Bulheller, G. Dan Pantoş, Jeremy K. M. Sanders and Jonathan D. Hirst
Physical Chemistry Chemical Physics 2009 vol. 11(Issue 29) pp:6060-6065
Publication Date(Web):15 May 2009
DOI:10.1039/B905187B
Amino acid derivatives of naphthalenediimide (NDI) form non-covalent polymers, which assemble into helical nanotubes through hydrogen bonding. The two enantiomers possess distinct circular dichroism (CD) spectra, but the bands could not be entirely ascribed to the effects of the monomer or a supramolecular structure. We calculate the CD of oligomers, using the (exciton) matrix method, based on ab initio results for the monomer. Several features in the experimental spectrum could be reproduced well and allow assignment of the electronic states of the oligomeric structure. The calculations provide evidence that the oligomer structures in the solid state and the solution phase are equivalent. The calculated spectra show a dependence on the oligomer length, which potentially could be exploited for the experimental characterization of the length of the helical nanotubes.
Co-reporter:Pooja Jain, Jonathan M. Garibaldi, Jonathan D. Hirst
Computational Biology and Chemistry 2009 Volume 33(Issue 3) pp:216-223
Publication Date(Web):June 2009
DOI:10.1016/j.compbiolchem.2009.04.004
We explore automation of protein structural classification using supervised machine learning methods on a set of 11,360 pairs of protein domains (up to 35% sequence identity) consisting of three secondary structure elements. Fifteen algorithms from five categories of supervised algorithms are evaluated for their ability to learn for a pair of protein domains, the deepest common structural level within the SCOP hierarchy, given a one-dimensional representation of the domain structures. This representation encapsulates evolutionary information in terms of sequence identity and structural information characterising the secondary structure elements and lengths of the respective domains. The evaluation is performed in two steps, first selecting the best performing base learners and subsequently evaluating boosted and bagged meta learners. The boosted random forest, a collection of decision trees, is found to be the most accurate, with a cross-validated accuracy of 97.0% and F-measures of 0.97, 0.85, 0.93 and 0.98 for classification of proteins to the Class, Fold, Super-Family and Family levels in the SCOP hierarchy. The meta learning regime, especially boosting, improved performance by more accurately classifying the instances from less populated classes.
Co-reporter:David Robinson, Nicholas A. Besley, Paul O’Shea and Jonathan D. Hirst
The Journal of Physical Chemistry B 2009 Volume 113(Issue 43) pp:14521-14528
Publication Date(Web):October 1, 2009
DOI:10.1021/jp9071108
5-Hydroxytryptophan is a non-natural amino acid that has attracted a lot of recent interest as a fluorescent probe of protein structure, dynamics, and function. We have investigated its fluorescence in various protein environments, using a decoupled quantum mechanics/molecular mechanics approach. Classical, all-atom molecular dynamics simulations of several proteins containing single tryptophans were performed for both the wild-type and the 5-hydroxy derivatives. The excited state of the fluorophore was described using parameters from complete active space self-consistent field calculations. Time-dependent density functional theory calculations on 5-hydroxytryptophan and a significant portion of its explicit immediate surrounding environment, sampled by the simulations, show that the emission energies of 5-hydroxytryptophan shift, depending on the strength of hydrogen bonding and π−π stacking interactions. This quantitative description of how the fluorescence responds to different protein environments should enhance the insight that fluorescence studies using 5-hydroxytryptophan can provide at a molecular level.
Co-reporter:Pooja Jain;Jonathan D Hirst
BMC Structural Biology 2009 Volume 9( Issue 1) pp:
Publication Date(Web):2009 December
DOI:10.1186/1472-6807-9-60
Classification of newly resolved protein structures is important in understanding their architectural, evolutionary and functional relatedness to known protein structures. Among various efforts to improve the database of Structural Classification of Proteins (SCOP), automation has received particular attention. Herein, we predict the deepest SCOP structural level that an unclassified protein shares with classified proteins with an equal number of secondary structure elements (SSEs).We compute a coefficient of dissimilarity (Ω) between proteins, based on structural and sequence-based descriptors characterising the respective constituent SSEs. For a set of 1,661 pairs of proteins with sequence identity up to 35%, the performance of Ω in predicting shared Class, Fold and Super-family levels is comparable to that of DaliLite Z score and shows a greater than four-fold increase in the true positive rate (TPR) for proteins sharing the Family level. On a larger set of 600 domains representing 200 families, the performance of Z score improves in predicting a shared Family, but still only achieves about half of the TPR of Ω. The TPR for structures sharing a Super-family is lower than in the first dataset, but Ω performs slightly better than Z score. Overall, the sensitivity of Ω in predicting common Fold level is higher than that of the DaliLite Z score.Classification to a deeper level in the hierarchy is specific and difficult. So the efficiency of Ω may be attractive to the curators and the end-users of SCOP. We suggest Ω may be a better measure for structure classification than the DaliLite Z score, with the caveat that currently we are restricted to comparing structures with equal number of SSEs.
Co-reporter:David Robinson, Nicholas A. Besley, Elizabeth A. M. Lunt, Paul O’Shea and Jonathan D. Hirst
The Journal of Physical Chemistry B 2009 Volume 113(Issue 8) pp:2535-2541
Publication Date(Web):February 5, 2009
DOI:10.1021/jp808943d
We have investigated the absorption and emission spectrum of 5-hydroxyindole in the gas phase and in various solvents. 5-Hydroxyindole is the fluorophore of the non-natural amino acid 5-hydroxytryptophan, which has attracted recent interest as a novel intrinsic probe for protein structure, dynamics, and function. Gas-phase and implicit solvent calculations were performed with multiconfigurational perturbation theory (CASPT2). An explicit solvent model was calculated using a decoupled quantum mechanics/molecular mechanics approach, utilizing recent advances in time-dependent density functional theory. The importance of hydrogen bonding is shown by comparing the implicit solvent model calculations with the explicit solvent calculations and experimental results. In line with other indole systems, the order of the 1L state peaks in 5-hydroxindole is 1Lb at lower energy than 1La, with the emitting state being 1La.
Co-reporter:Jonathan D. Hirst, Jeffry D. Madura
Journal of Molecular Graphics and Modelling 2009 Volume 28(Issue 1) pp:1
Publication Date(Web):August 2009
DOI:10.1016/j.jmgm.2009.07.003
Co-reporter:Benson M Spowage;Craig L Bruce;Jonathan D Hirst
Journal of Cheminformatics 2009 Volume 1( Issue 1) pp:
Publication Date(Web):2009 December
DOI:10.1186/1758-2946-1-22
The topological maximum cross correlation (TMACC) descriptors are alignment-independent 2D descriptors for the derivation of QSARs. TMACC descriptors are generated using atomic properties determined by molecular topology. Previous validation (J Chem Inf Model 2007, 47: 626-634) of the TMACC descriptor suggests it is competitive with the current state of the art.Here, we illustrate the interpretability of the TMACC descriptors, through the analysis of the QSARs of inhibitors of angiotensin converting enzyme (ACE) and dihydrofolate reductase (DHFR). In the case of the ACE inhibitors, the TMACC interpretation shows features specific to C-domain inhibition, which have not been explicitly identified in previous QSAR studies.The TMACC interpretation can provide new insight into the structure-activity relationships studied. Freely available, open source software for generating the TMACC descriptors can be downloaded from http://comp.chem.nottingham.ac.uk.
Co-reporter:Petros Kountouris;Jonathan D Hirst
BMC Bioinformatics 2009 Volume 10( Issue 1) pp:
Publication Date(Web):2009 December
DOI:10.1186/1471-2105-10-437
The prediction of the secondary structure of a protein is a critical step in the prediction of its tertiary structure and, potentially, its function. Moreover, the backbone dihedral angles, highly correlated with secondary structures, provide crucial information about the local three-dimensional structure.We predict independently both the secondary structure and the backbone dihedral angles and combine the results in a loop to enhance each prediction reciprocally. Support vector machines, a state-of-the-art supervised classification technique, achieve secondary structure predictive accuracy of 80% on a non-redundant set of 513 proteins, significantly higher than other methods on the same dataset. The dihedral angle space is divided into a number of regions using two unsupervised clustering techniques in order to predict the region in which a new residue belongs. The performance of our method is comparable to, and in some cases more accurate than, other multi-class dihedral prediction methods.We have created an accurate predictor of backbone dihedral angles and secondary structure. Our method, called DISSPred, is available online at http://comp.chem.nottingham.ac.uk/disspred/.
Co-reporter:Jonathan D. Hirst, Andrew J. Holder
Journal of Molecular Graphics and Modelling 2008 Volume 26(Issue 8) pp:vii
Publication Date(Web):June 2008
DOI:10.1016/S1093-3263(08)00041-7
Co-reporter:Benjamin M. Bulheller, Alison Rodger and Jonathan D. Hirst
Physical Chemistry Chemical Physics 2007 vol. 9(Issue 17) pp:2020-2035
Publication Date(Web):20 Feb 2007
DOI:10.1039/B615870F
Circular dichroism (CD) is an important technique in the structural characterisation of proteins, and especially for secondary structure determination. The CD of proteins can be calculated from first principles using the so-called matrix method, with an accuracy which is almost quantitative for helical proteins. Thus, for proteins of unknown structure, CD calculations and experimental data can be used in conjunction to aid structure analysis. Linear dichroism (LD) can be calculated using analogous methodology and has been used to establish the relative orientations of subunits in proteins and protein orientation in an environment such as a membrane. However, simple analysis of LD data is not possible, due to overlapping transitions. So coupling the calculations and experiment is an important strategy. In this paper, the use of LD for the determination of protein orientation and how these data can be interpreted with the aid of calculations, are discussed. We review methods for the calculation of CD spectra, focusing on semiempirical and ab initio parameter sets used in the matrix method. Lastly, a new web interface for online CD and LD calculation is presented.
Co-reporter:Jonathan D. Hirst
Journal of Molecular Graphics and Modelling 2007 Volume 26(Issue 3) pp:595
Publication Date(Web):October 2007
DOI:10.1016/j.jmgm.2007.04.003
Co-reporter:David M. Rogers, Jonathan D. Hirst, Edmond P.F. Lee, Timothy G. Wright
Chemical Physics Letters 2006 Volume 427(4–6) pp:410-413
Publication Date(Web):31 August 2006
DOI:10.1016/j.cplett.2006.07.022
We study different conformers of the toluene dimer using unconstrained geometry optimizations at the MP2 level of theory. We reoptimize these employing counterpoise-corrected MP2 gradients, and subsequently perform single-point counterpoise-corrected CCSD(T) interaction energy calculations. An antiparallel-stacked structure is found to be the most stable of the three isomers and has an interaction energy that is narrowly below that of a cross structure; a parallel-stacked structure is the least stable of the three isomers. We find no evidence for a stable T-shaped isomer, that is, no minimum on the potential energy surface corresponding to this structure.Non-counterpoise-corrected MP2/6-31++G∗∗ optimized geometries of the three toluene dimers. The CCSD(T) energies suggest the energy ordering is unchanged, with the lowest-energy isomer on the left.
Co-reporter:Mark T. Oakley;Benjamin M. Bulheller
Chirality 2006 Volume 18(Issue 5) pp:340-347
Publication Date(Web):23 MAR 2006
DOI:10.1002/chir.20264
Understanding the relationship between the amino acid sequence of a protein and its unique, compact three-dimensional structure is one of the grand challenges in molecular biophysics. One exciting approach to the protein-folding problem is fast time-resolved spectroscopy in the ultra-violet (UV). Time-resolved electronic circular dichroism (CD) spectroscopy offers resolution on a nanosecond (or faster) timescale, but does not provide the spatial resolution of techniques like X-ray crystallography or NMR. There is a need to underpin fast timescale spectroscopic studies of protein folding with a stronger theoretical foundation. We review some recent studies in this regard and briefly highlight how modern quantum chemical models of aromatic groups have improved the accuracy of calculations of protein CD spectra near-UV. On the other side of the far-UV, we describe calculations indicating that charge-transfer transitions are likely to be responsible for bands observed in the vacuum UV in protein CD. Chirality 18:340–347, 2006. © 2006 Wiley-Liss, Inc.
Co-reporter:James L. Melville, Benjamin I. Andrews, Barry Lygo and Jonathan D. Hirst
Chemical Communications 2004 (Issue 12) pp:1410-1411
Publication Date(Web):17 May 2004
DOI:10.1039/B402378A
A catalyst design methodology, utilizing combinatorial synthesis in parallel with chemometric analysis, is presented, which considers the 3D steric and electrostatic properties of substituents about a constant core structure.
Co-reporter:Tim M. Watson and Jonathan D. Hirst
Physical Chemistry Chemical Physics 2004 vol. 6(Issue 10) pp:2580-2587
Publication Date(Web):23 Feb 2004
DOI:10.1039/B315501C
The enkephalins are peptides with important biological activity. They are much more conformationally flexible than morphine, yet they bind to similar receptors with greater binding affinity. Their structures are therefore of particular interest. In this work we study the gas-phase low energy conformers of capped [Leu]enkephalin using the EDF1 density functional with the 6-31+G* basis set. The lowest energy structure found is a single β-bend structure. Calculated vibrational spectra indicate considerable scope for determination of low energy conformers from experiment.
Co-reporter:Tim M. Watson and Jonathan D. Hirst
Physical Chemistry Chemical Physics 2004 vol. 6(Issue 5) pp:998-1005
Publication Date(Web):19 Dec 2003
DOI:10.1039/B312181J
The infrared (IR) is an information rich region of molecular spectra. From characteristic absorptions it is possible to determine much structural information about molecules. This has been used to a large degree in the study of protein structure as a complementary technique to circular dichroism, X-ray crystallography and NMR. However, the current understanding of protein IR spectra is predicated largely on empirical structure–spectra relationships that are not infallible. Providing a theoretical basis for protein spectra will help to reduce these problems. In this paper, we review our recent work on accurate and computationally efficient small molecule gas phase calculations and examine how point charge environments can mimic features of proteins. We then develop a general automated strategy for applying the transition dipole coupling method for computing the IR spectra of proteins. Finally, we study the effect of conformational dynamics on the amide I band of concanavalin A.
Co-reporter:David M. Rogers
Chirality 2004 Volume 16(Issue 4) pp:234-243
Publication Date(Web):12 MAR 2004
DOI:10.1002/chir.20018
Understanding the relationship between the amino acid sequence of a protein and its unique, compact 3D structure is one of the grand challenges in molecular biophysics. One particularly exciting approach is time-resolved electronic circular dichroism (CD) spectroscopy, which offers resolution on a nanosecond (or faster) time scale, although it does not provide the spatial resolution of techniques like X-ray crystallography or NMR. The thrust of our work is to underpin fast time scale spectroscopic studies of protein folding with a stronger theoretical foundation. Ultimately, we seek to use molecular dynamics simulations to study the influence of conformational dynamics and conformational transitions on the electronic CD spectra of proteins. We discuss how improved quantum chemical models of individual chromophores, including aromatic sidechains, can be incorporated into calculations of the electronic structure of proteins and their CD. Chirality 16:234–243, 2004. © 2004 Wiley-Liss, Inc.
Co-reporter:Jonathan D. Hirst, T.John McNeany, Trevor Howe, Lewis Whitehead
Bioorganic & Medicinal Chemistry 2002 Volume 10(Issue 4) pp:1037-1041
Publication Date(Web):April 2002
DOI:10.1016/S0968-0896(01)00359-5
Several non-parametric regressors have been applied to modelling quantitative structure–activity relationship (QSAR) data. Performances were benchmarked against multilinear regression and the nonlinear method of smoothing splines. Variable selection was explored through systematic combinations of different variables and combinations of principal components. For the training set examined—539 inhibitors of the tyrosine kinase, Syk—the best two-descriptor model had a 5-fold cross-validated q2 of 0.43. This was generated by a multi-variate Nadaraya–Watson kernel estimator. A subsequent, independent, test set of 371 similar chemical entities showed the model had some predictive power. Other approaches did not perform as well. A modest increase in predictive ability can be achieved with three descriptors, but the resulting model is less easy to visualise. We conclude that non-parametric regression offers a potentially powerful approach to identifying predictive, low-dimensional QSARs.Graphic
Co-reporter:Zhijing Dang Dr.
Angewandte Chemie International Edition 2001 Volume 40(Issue 19) pp:
Publication Date(Web):2 OCT 2001
DOI:10.1002/1521-3773(20011001)40:19<3619::AID-ANIE3619>3.0.CO;2-4
More helix than peptide? The helical polypeptides have distinctive circular dichroism (CD) spectra, as shown in the graphic. The recent experimental observation of a peptide with an intense CD spectrum, which suggests a helical content of greater than 100 % is therefore highly anomalous. We present calculations from first principles which could explain this unusual observation.
Co-reporter:Zhijing Dang Dr.
Angewandte Chemie 2001 Volume 113(Issue 19) pp:
Publication Date(Web):2 OCT 2001
DOI:10.1002/1521-3757(20011001)113:19<3731::AID-ANGE3731>3.0.CO;2-V
Mehr als 100 % helicaler Anteil? Helicale Polypeptide haben charakteristische Circulardichroismus(CD)-Spektren (siehe Bild für eine typische Kurve). Ein kürzlich beobachtetes ungewöhnliches CD-Spektrum eines Peptids mit sehr intensiven Signalen ließ auf einen helicalen Anteil >100 % schließen – diese Anomalie könnte durch die vorliegende Untersuchung auf der Grundlage von Ab-initio-Rechnungen erklärt werden.
Co-reporter:James L. Melville, Iain H. Moal, Charles Baker-Glenn, Peter E. Shaw, Gerald Pattenden, Jonathan D. Hirst
Biophysical Journal (1 June 2007) Volume 92(Issue 11) pp:
Publication Date(Web):1 June 2007
DOI:10.1529/biophysj.106.103580
By the use of x-ray structures and flexible docking, we have developed the first in silico ligand-based view of the structural determinants of the binding of small molecule mimics of gelsolin, natural products bound to actin. Our technique highlights those residues on the actin binding site forming important hydrophobic and hydrogen-bonding interactions with the ligands. Significantly, through the flexible docking of toxin fragments, we have also identified potential residues on the actin binding site that have yet to be exploited. Guided by these observations, we have demonstrated that kabiramide C can be modified to produce a structure with a predicted binding energy increased by 20% while the molecular mass is reduced by 20%, clearly indicating the potential for future elaboration of structures targeting this important component of the cytoskeleton.
Co-reporter:Sonia Aguado-Ullate, John A. Baker, Vanessa González-González, Christian Müller, Jonathan D. Hirst and Jorge J. Carbó
Catalysis Science & Technology (2011-Present) 2014 - vol. 4(Issue 4) pp:NaN987-987
Publication Date(Web):2014/01/07
DOI:10.1039/C3CY00956D
The factors governing the activity in Rh-catalyzed hydroformylation were investigated using a set of computational tools. We performed DFT calculations on the phosphinine-modified Rh catalyst [HRh(CO)3(PC5H2R3)] and compared it to the phosphane-modified HRh(CO)3(PR3) and HRh(CO)2(PR3)2 complexes. The π-acceptor phosphinine ligand coordinates preferentially at the equatorial site of the pentacoordinated Rh complex with the heterocycle perpendicular to the equatorial plane, although the ligand freely rotates around the Rh–P bond. The overall energy barrier can be divided into the following contributions: alkene complex formation, alkene rotation and alkene insertion. In the absence of steric effects (model systems), the overall barrier correlates with the computed barrier for alkene rotation. This proves that π-acceptor ligands reduce back-donation to the alkene, leading to a lower rotational barrier and, consequently, to a higher activity. The Rh–P donor–acceptor interactions were quantified using a modified version of energy decomposition analysis (EDA). In Rh–phosphinine systems, the efficient directionality of the π-back-donation, rather than the overall acceptor ability, is responsible for the high catalytic activity. Introducing steric effects increases the energy required to coordinate the alkene, increasing the overall barrier. The factors governing the activity in Rh–monophosphane catalysts seem to be related to those derived for Rh–diphosphane during the development of a QSAR model (Catal. Sci. Technol. 2012, 2, 1694). To investigate whether the findings for mono- can be extrapolated to diphosphane ligands, we re-examined our previous QSAR model using the Topological Maximum Cross Correlation (TMACC) method based on easy-to-interpret 2D-descriptors. The TMACC descriptors highlight heteroatoms close to phosphorus as activity-increasing atoms, whereas highly substituted carbon atom groups are highlighted as activity-decreasing groups.
Co-reporter:Zhuo Li
Chemical Science (2010-Present) 2017 - vol. 8(Issue 6) pp:
Publication Date(Web):2017/05/30
DOI:10.1039/C7SC00586E
Vibrational structure in the near-UV circular dichroism (CD) spectra of proteins is an important source of information on protein conformation and can be exploited to study structure and folding. A fully quantitative theory of the relationship between protein conformation and optical spectroscopy would facilitate deeper interpretation of and insight into biophysical and simulation studies of protein dynamics and folding. We have developed new models of the aromatic side chain chromophores toluene, p-cresol and 3-methylindole, which incorporate ab initio calculations of the Franck–Condon effect into first principles calculations of CD using an exciton approach. The near-UV CD spectra of 40 proteins are calculated with the new parameter set and the correlation between the computed and the experimental intensity from 270 to 290 nm is much improved. The contribution of individual chromophores to the CD spectra has been calculated for several mutants and in many cases helps rationalize changes in their experimental spectra. Considering conformational flexibility by using families of NMR structures leads to further improvements for some proteins and illustrates an informative level of sensitivity to side chain conformation. In several cases, the near-UV CD calculations can distinguish the native protein structure from a set of computer-generated misfolded decoy structures.
Co-reporter:Benjamin M. Bulheller, G. Dan Pantoş, Jeremy K. M. Sanders and Jonathan D. Hirst
Physical Chemistry Chemical Physics 2009 - vol. 11(Issue 29) pp:NaN6065-6065
Publication Date(Web):2009/05/15
DOI:10.1039/B905187B
Amino acid derivatives of naphthalenediimide (NDI) form non-covalent polymers, which assemble into helical nanotubes through hydrogen bonding. The two enantiomers possess distinct circular dichroism (CD) spectra, but the bands could not be entirely ascribed to the effects of the monomer or a supramolecular structure. We calculate the CD of oligomers, using the (exciton) matrix method, based on ab initio results for the monomer. Several features in the experimental spectrum could be reproduced well and allow assignment of the electronic states of the oligomeric structure. The calculations provide evidence that the oligomer structures in the solid state and the solution phase are equivalent. The calculated spectra show a dependence on the oligomer length, which potentially could be exploited for the experimental characterization of the length of the helical nanotubes.
Co-reporter:Benjamin M. Bulheller, Alison Rodger and Jonathan D. Hirst
Physical Chemistry Chemical Physics 2007 - vol. 9(Issue 17) pp:NaN2035-2035
Publication Date(Web):2007/02/20
DOI:10.1039/B615870F
Circular dichroism (CD) is an important technique in the structural characterisation of proteins, and especially for secondary structure determination. The CD of proteins can be calculated from first principles using the so-called matrix method, with an accuracy which is almost quantitative for helical proteins. Thus, for proteins of unknown structure, CD calculations and experimental data can be used in conjunction to aid structure analysis. Linear dichroism (LD) can be calculated using analogous methodology and has been used to establish the relative orientations of subunits in proteins and protein orientation in an environment such as a membrane. However, simple analysis of LD data is not possible, due to overlapping transitions. So coupling the calculations and experiment is an important strategy. In this paper, the use of LD for the determination of protein orientation and how these data can be interpreted with the aid of calculations, are discussed. We review methods for the calculation of CD spectra, focusing on semiempirical and ab initio parameter sets used in the matrix method. Lastly, a new web interface for online CD and LD calculation is presented.
Co-reporter:Hainam Do, Richard J. Wheatley and Jonathan D. Hirst
Physical Chemistry Chemical Physics 2010 - vol. 12(Issue 40) pp:NaN13272-13272
Publication Date(Web):2010/09/07
DOI:10.1039/C0CP00620C
1-1-1-2-tetrafluoroethane (R134a) is one of the most commonly used refrigerants. Its thermophysical properties are important for evaluating the performance of refrigeration cycles. These can be obtained via computer simulation, with an insight into the microscopic structure of the liquid, which is not accessible to experiment. In this paper, vapour–liquid equilibrium properties of R134a and its liquid microscopic structure are investigated using coupled–decoupled configurational-bias Monte Carlo simulation in the Gibbs ensemble, with a recent potential [J. Phys. Chem. B 2009, 113, 178]. We find that the simulations agree well with the experimental data, except at the vicinity of the critical region. Liquid R134a packs like liquid argon, with a coordination number in the first solvation shell of 12 at 260 K. The nearest neighbours prefer to be localized in three different spaces around the central molecule, in such a manner that the dipole moments are in a parallel alignment. Analysis of the pair interaction energy shows clear association of R134a molecules, but no evidence for C–H⋯F type hydrogen bonding is found. The above findings should be of relevance to a broad range of fluoroalkanes.
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![Formamide,N-[11-(14,16-dihydroxy-10-methoxy-11,21-dimethyl-12,18-dioxo-3,7,19,27-tetraoxa-29,30,31-triazatetracyclo[24.2.1.12,5.16,9]hentriaconta-2(31),4,6(30),8,24,26(29),28-heptaen-20-yl)-4,10-dimethoxy-5,9-dimethyl-6-oxo-1-undecen-1-yl]-N-methyl-](http://img.cochemist.com/ccimg/149500/149420-76-8_b.png)
![Pyridinium,4-[2-[6-(dioctylamino)-2-naphthalenyl]ethenyl]-1-(3-sulfopropyl)-, inner salt](http://img.cochemist.com/ccimg/157200/157134-53-7.png)
![Pyridinium,4-[2-[6-(dioctylamino)-2-naphthalenyl]ethenyl]-1-(3-sulfopropyl)-, inner salt](http://img.cochemist.com/ccimg/157200/157134-53-7_b.png)
![Serine,N,N,O-trimethyl-,(3E,5E,8R,9S,10R,11R,14S,15E,18R,20R,21E,24S)-24-[(1S,2S,3S,6R,7S,8R,9R,10E)-8-(acetyloxy)-6-[2-(dimethylamino)-1-oxopropoxy]-11-(formylmethylamino)-2-hydroxy-1,3,7,9-tetramethyl-10-undecen-1-yl]-10-hydroxy-14,20-dimethoxy-9,11,15,18-tetramethyl-2-oxooxacyclotetracosa-3,5,15,21-tetraen-8-ylester](http://img.cochemist.com/ccimg/152000/151923-84-1.png)
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![3,5,9-Trioxa-4-phosphapentacosan-1-aminium,4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(1-oxohexadecyl)oxy]-, inner salt, 4-oxide](http://img.cochemist.com/ccimg/2700/2644-64-6.png)
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