Dataset Information

Microscopic events in ?-hairpin folding from alternative unfolded ensembles.

ABSTRACT: We have performed the first unbiased folding simulations of the GB1 hairpin in explicit solvent, using hundreds of microsecond-long molecular dynamics simulations (total time: 0.7 ms). Our simulations are initiated from two sets of structures. Starting from an equilibrium unfolded state, we obtain single-exponential folding kinetics with rate coefficients in good agreement (T=350 K) or within an order of magnitude (T=300 K) of the experimental values. However, simulations initiated from unfolded configurations lacking secondary structure result in biexponential kinetics with an additional fast nanosecond kinetic mode. This mode can strongly bias the folding rate estimated from the mean first passage time, when the trials are much shorter than the folding time. We find that the mechanism of the hairpin folding is insensitive to the details of the initial unfolded ensemble and is initiated by correct formation of the turn of the hairpin, followed by the formation of the native hydrogen bonds and hydrophobic contacts, consistent with experimental -value analysis. Subsequent native interactions can be formed either from the turn or from the hairpin termini, helping to explain an apparent discrepancy in experimental results. From our simulations, we also obtain the transition path durations, a critical parameter for single molecule experiments aiming to resolve events along folding pathways. The lengths of transition paths span a wide range, from 50 ps to 140 ns, at 300 K.

SUBMITTER: Best RB

PROVIDER: S-EPMC3131341 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Microscopic events in β-hairpin folding from alternative unfolded ensembles.

Best Robert B RB Mittal Jeetain J

Proceedings of the National Academy of Sciences of the United States of America 20110620 27

We have performed the first unbiased folding simulations of the GB1 hairpin in explicit solvent, using hundreds of microsecond-long molecular dynamics simulations (total time: 0.7 ms). Our simulations are initiated from two sets of structures. Starting from an equilibrium unfolded state, we obtain single-exponential folding kinetics with rate coefficients in good agreement (T=350 K) or within an order of magnitude (T=300 K) of the experimental values. However, simulations initiated from unfolded ...[more]

PMID: 21690352

Similar Datasets

Project description:The study of protein folding mechanisms continues to be one of the most challenging problems in computational biology. Currently, the protein folding mechanism is often characterized by calculating the free energy landscape versus various reaction coordinates, such as the fraction of native contacts, the radius of gyration, RMSD from the native structure, and so on. In this paper, we present a combinatorial pattern discovery approach toward understanding the global state changes during the folding process. This is a first step toward an unsupervised (and perhaps eventually automated) approach toward identification of global states. The approach is based on computing biclusters (or patterned clusters)-each cluster is a combination of various reaction coordinates, and its signature pattern facilitates the computation of the Z-score for the cluster. For this discovery process, we present an algorithm of time complexity c in RO((N + nm) log n), where N is the size of the output patterns and (n x m) is the size of the input with n time frames and m reaction coordinates. To date, this is the best time complexity for this problem. We next apply this to a beta-hairpin folding trajectory and demonstrate that this approach extracts crucial information about protein folding intermediate states and mechanism. We make three observations about the approach: (1) The method recovers states previously obtained by visually analyzing free energy surfaces. (2) It also succeeds in extracting meaningful patterns and structures that had been overlooked in previous works, which provides a better understanding of the folding mechanism of the beta-hairpin. These new patterns also interconnect various states in existing free energy surfaces versus different reaction coordinates. (3) The approach does not require calculating the free energy values, yet it offers an analysis comparable to, and sometimes better than, the methods that use free energy landscapes, thus validating the choice of reaction coordinates. (An abstract version of this work was presented at the 2005 Asia Pacific Bioinformatics Conference [1].).

Dataset Information

Microscopic events in ?-hairpin folding from alternative unfolded ensembles.

Publications

Microscopic events in β-hairpin folding from alternative unfolded ensembles.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets