Abstract
The folding process of the 20 residue Trp-cage mini-protein was investigated using standard temperature replica exchange molecular dynamics (T-RexMD) simulation and a biasing potential RexMD (BP-RexMD) method. In contrast to several conventional molecular dynamics simulations, both RexMD methods sampled conformations close to the native structure after 10–20 ns simulation time as the dominant conformational states. In contrast, to T-RexMD involving 16 replicas the BP-RexMD method achieved very similar sampling results with only five replicas. The result indicates that the BP-RexMD method is well suited to study folding processes of proteins at a significantly smaller computational cost, compared to T-RexMD. Both RexMD methods sampled not only similar final states but also agreed on the sampling of intermediate conformations during Trp-cage folding. The analysis of the sampled potential energy contributions indicated that Trp-cage folding is favored by both van der Waals and to a lesser degree electrostatic contributions. Folding does not introduce any significant sterical strain as reflected by similar energy distributions of bonded energy terms (bond length, bond angle and dihedral angle) of folded and unfolded Trp-cage structures.
Highlights
Realistic computer simulation of the structure formation process of proteins is a great challenge of molecular biophysics and structural biology
RexMD is the fact the energy differences are only affected by the force field term that changes upon going from one replica to another replica run
Rmsd of five independent conventional MD (cMD) simulations starting from an extended Trp-cage structure with different initial atomic velocities. (B) Rmsd of conformations sampled during the TRexMD started from the same extended conformation. (C)
Summary
Realistic computer simulation of the structure formation process of proteins is a great challenge of molecular biophysics and structural biology. Molecular dynamics (MD) simulations have been widely used for studying folding processes of peptides and small proteins, including the characterization of folding pathways and intermediate states [1,2,3,4,5]. The currently possible time scales of ~100 ns still limit the applicability of MD simulation to small proteins and simulation times that are insufficient to study the folding process systematically. At room temperature a standard MD simulation may be trapped into a locally stable conformation. Conformational transitions between these stable states are rare during conventional MD (cMD) simulations [1,2,3,4,5,6]. A variety of methods like simulated annealing [7], potential scaling [8,9,10,11,12,13,14,15], locally enhanced sampling [16], or parallel tempering [17,18,19]
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