X-ray crystallographic snapshots have shown that conformational changes of a tetraglycine loop in the active site of formyl-CoA:oxalate CoA transferase (FRC) play an important role in the catalytic cycle of the enzyme. Orthogonal space random walk (OSRW) simulations have been applied to obtain quantitative computational estimates of the relative free energy of the “open” and “closed” conformations of this loop together with the energetic barrier for interconversion of these states in wild type FRC. These OSRW calculations not only show that the two conformations have similar free energies but also predict a barrier that is consistent with the observed turnover number of the enzyme. In an effort to quantitate the importance of specific residues in the tetraglycine loop, OSRW simulations have also been performed on the G258A, G259A, G260A, and G261A FRC variants both to examine the energetic effects of replacing each glycine residue and to correlate the computed energies with kinetic and structural observations. In enzymes with substantially reduced catalytic efficiency (kcat/KM), the OSRW simulations reveal the adoption of additional low energy loop conformations. In the case of the G260A FRC variant, the new conformation identified by simulation is similar to that observed in the X-ray crystal structure of the protein. These results provide further evidence for the power of the OSRW method in sampling conformational space and, hence, in providing quantitative free energy estimates for the conformations adopted by functionally important active site loops. In addition, these simulations model the motions of side chains that are correlated with changes in loop conformation thereby permitting access to long time-scale motions through the use of nanosecond simulations.

Counterions play an important role in biomolecular functions. Although molecular dynamics simulations have been applied on various nucleic acids, accurate and efficient descriptions of ion motions around DNA or RNA are still challenging, largely due to ions’ slow mobility. Here, a variant Hamiltonian replica exchange method was developed to achieve efficient sampling of ion motions. Based on the present approach, the results from our model study on classical Drew–Dickerson B-DNA dodecamer show remarkable agreements with experimental measurements and nonlinear Poisson–Boltzmann predictions. Due to the employment of this variant Hamiltonian replica exchange method, these amazing agreements can be achieved within a short simulation time (900 ps).A variant Hamiltonian replica exchange sampling method is developed to facilitate the entropic barrier crossings during the sampling of ions around DNA.

Free energy calculations play an essential role in computational physics. As often observed, based on the same set of simulated data, various free energy estimators, such as thermodynamic integration, overlap histogramming, and free energy perturbation, usually have different convergence behavior. In the present work, a λ-WHAM approach is developed to forge such missing link by refining the energy derivative histograms with the maximal likelihood treatment. Using these λ-WHAM generated energy derivative histograms, free energy estimation efficiency and accuracy are optimally improved; more interestingly, with this additional λ-WHAM component, these seemingly different theoretical approaches become identical.A λ-WHAM strategy is introduced to optimally generate the energy derivative histograms for the free energy simulation estimations.