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Dual folding pathways of an alpha/beta protein from all-atom ab initio folding simulations.

ABSTRACT: Successful ab initio folding of proteins with both alpha-helix and beta-sheet requires a delicate balance among a variety of forces in the simulation model, which may explain that the successful folding of any alpha/beta proteins to within experimental error has yet to be reported. Here we demonstrate that it is an achievable goal to fold alpha/beta proteins with a force field emphasizing the balance between the two major secondary structures. Using our newly developed force field, we conducted extensive ab initio folding simulations on an alpha/beta protein full sequence design (FSD) employing both conventional molecular dynamics and replica exchange molecular dynamics in combination with a generalized-Born solvation model. In these simulations, the folding of FSD to the native state with high population (>64.2%) and high fidelity (C(alpha)-Root Mean Square Deviation of 1.29 A for the most sampled conformation when compared to the experimental structure) was achieved. The folding of FSD was found to follow two pathways. In the major pathway, the folding started from the formation of the helix. In the minor pathway, however, folding of the beta-hairpin started first. Further examination revealed that the helix initiated from the C-terminus and propagated toward the N-terminus. The formation of the hydrophobic contacts coincided with the global folding. Therefore the hydrophobic force does not appear to be the driving force of the folding of this protein.

SUBMITTER: Lei H

PROVIDER: S-EPMC2780466 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Dual folding pathways of an alpha/beta protein from all-atom ab initio folding simulations.

Lei Hongxing H Wang Zhi-Xiang ZX Wu Chun C Duan Yong Y

The Journal of chemical physics 20091001 16

Successful ab initio folding of proteins with both alpha-helix and beta-sheet requires a delicate balance among a variety of forces in the simulation model, which may explain that the successful folding of any alpha/beta proteins to within experimental error has yet to be reported. Here we demonstrate that it is an achievable goal to fold alpha/beta proteins with a force field emphasizing the balance between the two major secondary structures. Using our newly developed force field, we conducted ...[more]

PMID: 19894980

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Project description:Reaching the native states of small proteins, a necessary step towards a comprehensive understanding of the folding mechanisms, has remained a tremendous challenge to ab initio protein folding simulations despite the extensive effort. In this work, the folding process of the B domain of protein A (BdpA) has been simulated by both conventional and replica exchange molecular dynamics using AMBER FF03 all-atom force field. Started from an extended chain, a total of 40 conventional (each to 1.0 micros) and two sets of replica exchange (each to 200.0 ns per replica) molecular dynamics simulations were performed with different generalized-Born solvation models and temperature control schemes. The improvements in both the force field and solvent model allowed successful simulations of the folding process to the native state as demonstrated by the 0.80 A C(alpha) root mean square deviation (RMSD) of the best folded structure. The most populated conformation was the native folded structure with a high population. This was a significant improvement over the 2.8 A C(alpha) RMSD of the best nativelike structures from previous ab initio folding studies on BdpA. To the best of our knowledge, our results demonstrate, for the first time, that ab initio simulations can reach the native state of BdpA. Consistent with experimental observations, including Phi-value analyses, formation of helix II/III hairpin was a crucial step that provides a template upon which helix I could form and the folding process could complete. Early formation of helix III was observed which is consistent with the experimental results of higher residual helical content of isolated helix III among the three helices. The calculated temperature-dependent profile and the melting temperature were in close agreement with the experimental results. The simulations further revealed that phenylalanine 31 may play critical to achieve the correct packing of the three helices which is consistent with the experimental observation. In addition to the mechanistic studies, an ab initio structure prediction was also conducted based on both the physical energy and a statistical potential. Based on the lowest physical energy, the predicted structure was 2.0 A C(alpha) RMSD away from the experimentally determined structure.

Dataset Information

Dual folding pathways of an alpha/beta protein from all-atom ab initio folding simulations.

Publications

Dual folding pathways of an alpha/beta protein from all-atom ab initio folding simulations.

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