Browsing by Subject "umbrella sampling simulations"

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    Finite Temperature String Method with Umbrella Sampling: Application on a Side Chain Flipping in Mhp1 Transporter
    (ACS, 2017) Song, Hyun Deok; Zhu, Fangqiang; Physics, School of Science
    Protein conformational change is of central importance in molecular biology. Here we demonstrate a computational approach to characterize the transition between two metastable conformations in all-atom simulations. Our approach is based on the finite temperature string method, and the implementation is essentially a generalization of umbrella sampling simulations with Hamiltonian replica exchange. We represent the transition pathway by a curve in the conformational space, with the curve parameter taken as the reaction coordinate. Our approach can efficiently refine a transition pathway and compute a one-dimensional free energy as a function of the reaction coordinate. A diffusion model can then be used to calculate the forward and backward transition rates, the major kinetic quantities for the transition. We applied the approach on a local transition in the ligand-free Mhp1 transporter, between its outward-facing conformation and an intermediate conformation with the side chain of Phe305 flipped to the outside of the protein. Our simulations predict that the flipped-out position of this side chain has a free energy 6.5 kcal/mol higher than the original position in the crystal structure, and that the forward and backward transition rates are in the millisecond and submicrosecond time scales, respectively.
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    Thermodynamics of Protein Folding Studied by Umbrella Sampling along a Reaction Coordinate of Native Contacts
    (ACS, 2017) Meshkin, Hamed; Zhu, Fangqiang; Physics, School of Science
    Spontaneous transitions between the native and non-native protein conformations are normally rare events that hardly take place in typical unbiased molecular dynamics simulations. It was recently demonstrated that such transitions can be well described by a reaction coordinate, Q, that represents the collective fraction of the native contacts between the protein atoms. Here we attempt to use this reaction coordinate to enhance the conformational sampling. We perform umbrella sampling simulations with biasing potentials on Q for two model proteins, Trp-Cage and BBA, using the CHARMM force field. Hamiltonian replica exchange is implemented in these simulations to further facilitate the sampling. The simulations appear to have reached satisfactory convergence, resulting in unbiased free energies as a function of Q. In addition to the native structure, multiple folded conformations are identified in the reconstructed equilibrium ensemble. Some conformations without any native contacts nonetheless have rather compact geometries and are stabilized by hydrogen bonds not present in the native structure. Whereas the enhanced sampling along Q reasonably reproduces the equilibrium conformational space, we also find that the folding of an α-helix in Trp-Cage is a slow degree of freedom orthogonal to Q and therefore cannot be accelerated by biasing the reaction coordinate. Overall, we conclude that whereas Q is an excellent parameter to analyze the simulations, it is not necessarily a perfect reaction coordinate for enhanced sampling, and better incorporation of other slow degrees of freedom may further improve this reaction coordinate.