Ab Initio Folding of Helix Bundle Proteins Using Molecular Dynamics Simulations

Abstract

We have demonstrated that ab initio fast folding simulations at 400 K using a GB implicit solvent model with an all-atom based force field can describe the spontaneous formation of nativelike structures for the 36-residue villin headpiece and the 46-residue fragment B of Staphylococcal protein A. An implicit solvent model combined with high-temperature MD makes it possible to perform direct folding simulations of small- to medium-sized proteins by reducing the computational requirements tremendously. In the early stage of folding of the villin headpiece and protein A, initial hydrophobic collapse and rapid formation of helices were found to play important roles. For protein A, the third helix forms first in the early stage of folding and exhibits higher stability. The free energy profiles calculated from the folding simulations suggested that both of the helix-bundle proteins show a two-state thermodynamic behavior and protein A exhibits rather broad native basins.

Testing protein-folding simulations by experiment: B domain of protein A

“…Linhananta and Zhou (30) extended the previous studies by using an all-heavy-atom representation to give a detailed view of the transition state, which is dominated by an on-pathway intermediate consisting of an H2-H3 microdomain. Pak and colleagues obtained similar results by using all-atom molecular dynamics with an implicit solvent model (34). Myers and Oas (8) and Weaver and colleagues (33) independently have calculated that the diffusion-collision model reproduces the ultra-fast-folding experimental data.…”

“…Numerous simulations have been made by using various techniques, including offlattice, all-atom molecular dynamics, and conformational sampling methods (8,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The suggested folding mechanisms range from diffusion-collision to hydrophobic collapse models, and the predictions differ in the order of events on the folding pathway.…”

Molecular Dynamics with the United-Residue Model of Polypeptide Chains. I. Lagrange Equations of Motion and Tests of Numerical Stability in the Microcanonical Mode

“…Consequently, we consider only K x . (10) The right-hand side of eq 10 is exact if it is assumed (i) that the transformation from one UNRES conformation to another one is infinitely slow compared to the motion of the "fast" degrees of freedom and (ii) that, at each point of the UNRES trajectory, the UNRES degrees of freedom act as constraints. 57 However, while condition i can be considered to be reasonably satisfied, the UNRES degrees of freedom should be considered as average values of the respective coordinates rather than exact constraints.…”

Latest folding game results: Protein A barely frustrates computationalists

“…Brooks and colleagues (12,13) and Garcia and Onuchic (14) suggest that helices H1 and H2 are mostly involved in the structures formed in the TSE, in close agreement with experimental findings. Other groups (15)(16)(17)(18)(19)(20)(21)(22)(23) highlight the role of helix H3, which has been found to be the most stable, in isolation, experimentally. The dominant TSE configurations in the latter simulations involved contacts between H2 and H3.…”

“…The protein also folds fast, so computer studies have the best chance of success. Numerous simulations were carried out (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) without extensive laboratory kinetic studies at the residue level to influence the work. It is thus interesting to see how well the computationalists have been able to predict the folding mechanism without much biasing data.…”