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Sampling of Protein Folding Transitions: Multicanonical Versus Replica Exchange Molecular Dynamics.

ABSTRACT: We compare the efficiency of multicanonical and replica exchange molecular dynamics for the sampling of folding/unfolding events in simulations of proteins with end-to-end ?-sheet. In Go-model simulations of the 75-residue MNK6, we observe improvement factors of 30 in the number of folding/unfolding events of multicanonical molecular dynamics over replica exchange molecular dynamics. As an application, we use this enhanced sampling to study the folding landscape of the 36-residue DS119 with an all-atom physical force field and implicit solvent. Here, we find that the rate-limiting step is the formation of the central helix that then provides a scaffold for the parallel ?-sheet formed by the two chain ends.

SUBMITTER: Jiang P

PROVIDER: S-EPMC3815463 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Sampling of Protein Folding Transitions: Multicanonical Versus Replica Exchange Molecular Dynamics.

Jiang Ping P Yaşar Fatih F Hansmann Ulrich H E UH

Journal of chemical theory and computation 20130801 8

We compare the efficiency of multicanonical and replica exchange molecular dynamics for the sampling of folding/unfolding events in simulations of proteins with end-to-end <i>β</i>-sheet. In Go-model simulations of the 75-residue MNK6, we observe improvement factors of 30 in the number of folding/unfolding events of multicanonical molecular dynamics over replica exchange molecular dynamics. As an application, we use this enhanced sampling to study the folding landscape of the 36-residue DS119 wi ...[more]

PMID: 24198735

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Project description:Three algorithms, namely a Replica Exchange method (REM), a Replica Exchange Multicanonical method (REMUCA), and Replica Exchange Multicanonical with Replica Exchange (REMUCAREM), were implemented with the coarse-grained united-residue force field (UNRES) in both Monte Carlo and Molecular Dynamics versions. The MD algorithms use the constant-temperature Berendsen thermostat, with the velocity Verlet algorithm and variable time step. The algorithms were applied to one peptide (20 residues of Alanine with free ends; ala(20)) and two small proteins, namely an ?-helical protein of 46 residues (the B-domain of the staphylococal protein A; 1BDD), and an ?+?-protein of 48 residues (the E. Coli Mltd Lysm Domain; 1E0G). Calculated thermodynamic averages, such as canonical average energy and heat capacity, are in good agreement among all simulations for poly-L-alanine, showing that the algorithms were implemented correctly, and that all three algorithms are equally effective for small systems. For protein A, all algorithms performed reasonably well, although some variability in the calculated results was observed whereas, for a more complicated ?+?-protein (1E0G), only Replica Exchange was capable of producing reliable statistics for calculating thermodynamic quantities. Finally, from the Replica Exchange molecular dynamics results, we calculated free energy maps as functions of RMSD and radius of gyration for different temperatures. The free energy calculations show correct folding behavior for poly-L-alanine and protein A while, for 1E0G, the native structure had the lowest free energy only at very low temperatures. Hence, the entropy contribution for 1E0G is larger than that for protein A at the same temperature. A larger contribution from entropy means that there are more accessible conformations at a given temperature, making it more difficult to obtain an efficient coverage of conformational space to obtain reliable thermodynamic properties. At the same temperature, ala(20) has the smallest entropy contribution, followed by protein A, and then by 1E0G.

Dataset Information

Sampling of Protein Folding Transitions: Multicanonical Versus Replica Exchange Molecular Dynamics.

Publications

Sampling of Protein Folding Transitions: Multicanonical Versus Replica Exchange Molecular Dynamics.

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