Folding of small proteins using a single continuous potential

Kim, Seung‐Yeon; Lee, Julian; Lee, Jooyoung

doi:10.1063/1.1689643

Cited by 21 publications

(25 citation statements)

References 31 publications

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“…When we define helix formation by native backbone hydrogen bonds, its order is H3, H1, and H2. In the recent computational work of Kim et al, 41 H1 is suggested to be the most stable. The appearance of sustained backbone hydrogen bonds coincides with the beginning of the second folding stage (j > 950).…”

Section: Order Of Helix Formationmentioning

confidence: 99%

Dynamic folding pathway models of the villin headpiece subdomain (HP‐36) structure

2009

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Abstract:We have investigated the folding pathway of the 36-residue villin headpiece subdomain (HP-36) by actionderived molecular dynamics simulations. The folding is initiated by hydrophobic collapse, after which the concurrent formation of full tertiary structure and α-helical secondary structure is observed. The collapse is observed to be associated with a couple of specific native contacts contrary to the conventional nonspecific hydrophobic collapse model. Stable secondary structure formation after the collapse suggests that the folding of HP-36 follows neither the framework model nor the diffusion-collision model. The C-terminal helix forms first, followed by the N-terminal helix positioned in its native orientation. The short middle helix is shown to form last. Signs for multiple folding pathways are also observed.

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Section: Order Of Helix Formationmentioning

confidence: 99%

Dynamic folding pathway models of the villin headpiece subdomain (HP‐36) structure

2009

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“…20,21 The ab initio folding of FSD has also been attempted by Pak and co-workers 22 and Lee and co-workers. 23 Recently, Hansmann and co-worker 24 and Wang and co-workers 25 applied replica exchange molecular dynamics ͑REMD͒ to the folding study of FSD. The protein in those simulations mostly drifted away from the experimental structure and the most populated conformation was centered at 2.5-4.0 Å, indicating significant artifact in the force fields used in those simulations that made the interpretation of the observed folding events somewhat challenging.…”

Section: 2mentioning

confidence: 99%

Dual folding pathways of an α/β protein from all-atom ab initio folding simulations

Lei

Wang

et al. 2009

The Journal of Chemical Physics

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Successful ab initio folding of proteins with both ␣-helix and ␤-sheet requires a delicate balance among a variety of forces in the simulation model, which may explain that the successful folding of any ␣ / ␤ proteins to within experimental error has yet to be reported. Here we demonstrate that it is an achievable goal to fold ␣ / ␤ 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 ␣ / ␤ protein full sequence design ͑FSD͒ 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 ͑Ͼ64.2%͒ and high fidelity ͑C ␣ -Root Mean Square Deviation of 1.29 Å for the most sampled conformation when compared to the experimental structure͒ 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 ␤-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.

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“…In the endeavor of obtaining a quantitative agreement between theory and experiments, two small ␣-helical proteins have played a central role, namely the B domain of protein A from Staphylococcus aurues and the Villin headpiece subdomain from chicken. Although these proteins belong to different SCOP fold classes (5), both have simple three-helix bundle native topologies and fold autonomously on the microsecond time scale (6, 7), which makes them ideal test cases for protein simulations and numerous simulation studies, ranging from simple C ␣ Go-type to all-atom models with explicit water, have been undertaken for both protein A (8-21) and Villin (16,17,[22][23][24][25][26][27][28][29].Important advances have been made toward agreements with experiments for both proteins, but several key issues remain unresolved (6, 30, 31). The need for additional studies also is emphasized by recent experiments.…”

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confidence: 99%

Universality and diversity of folding mechanics for three-helix bundle proteins

Yang

Wallin

Shakhnovich

2008

Proc. Natl. Acad. Sci. U.S.A.

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In this study we evaluate, at full atomic detail, the folding processes of two small helical proteins, the B domain of protein A and the Villin headpiece. Folding kinetics are studied by performing a large number of ab initio Monte Carlo folding simulations using a single transferable all-atom potential. Using these trajectories, we examine the relaxation behavior, secondary structure formation, and transition-state ensembles (TSEs) of the two proteins and compare our results with experimental data and previous computational studies. To obtain a detailed structural information on the folding dynamics viewed as an ensemble process, we perform a clustering analysis procedure based on graph theory. Moreover, rigorous pfold analysis is used to obtain representative samples of the TSEs and a good quantitative agreement between experimental and simulated ⌽ values is obtained for protein A. ⌽ values for Villin also are obtained and left as predictions to be tested by future experiments. Our analysis shows that the two-helix hairpin is a common partially stable structural motif that gets formed before entering the TSE in the studied proteins. These results together with our earlier study of Engrailed Homeodomain and recent experimental studies provide a comprehensive, atomic-level picture of folding mechanics of three-helix bundle proteins.transition state ensemble ͉ Villin ͉ protein A A n eventual solution to the protein-folding problem will involve a close calibration of theoretical methods to experimental data (1-4). In the endeavor of obtaining a quantitative agreement between theory and experiments, two small ␣-helical proteins have played a central role, namely the B domain of protein A from Staphylococcus aurues and the Villin headpiece subdomain from chicken. Although these proteins belong to different SCOP fold classes (5), both have simple three-helix bundle native topologies and fold autonomously on the microsecond time scale (6, 7), which makes them ideal test cases for protein simulations and numerous simulation studies, ranging from simple C ␣ Go-type to all-atom models with explicit water, have been undertaken for both protein A (8-21) and Villin (16,17,[22][23][24][25][26][27][28][29].Important advances have been made toward agreements with experiments for both proteins, but several key issues remain unresolved (6, 30, 31). The need for additional studies also is emphasized by recent experiments. Fersht et al. (31,32) performed a comprehensive mutational analysis on protein A by obtaining ⌽ values at Ͻ30 aa positions, providing an important benchmark for simulation studies. The obtained ⌽ values suggest that the transition-state ensemble (TSE) is characterized mainly by a well formed H2 (we denote the three individual helices from N-to C-terminal by H1, H2, and H3, following previous convention) stabilized by hydrophobic interactions with H1. Recent experimental studies of Villin (6, 33) have focused mainly on achieving fast-folding mutants, although new biophysical characterization of wild-type Villin a...

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Folding of small proteins using a single continuous potential

Cited by 21 publications

References 31 publications

Dynamic folding pathway models of the villin headpiece subdomain (HP‐36) structure

Dynamic folding pathway models of the villin headpiece subdomain (HP‐36) structure

Dual folding pathways of an α/β protein from all-atom ab initio folding simulations

Universality and diversity of folding mechanics for three-helix bundle proteins

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