Dataset Information

Psi-constrained simulations of protein folding transition states: implications for calculating.

ABSTRACT: Psi-analysis has been used to identify interresidue contacts in the transition state ensemble (TSE) of ubiquitin and other proteins. The magnitude of psi depends on the degree to which an inserted bihistidine (biHis) metal ion binding site is formed in the TSE. A psi equal to zero or one indicates that the biHis site is absent or fully native-like, respectively, while a fractional psi implies that in the TSE, the biHis site recovers only part of the binding-induced stabilization of the native state. All-atom Langevin dynamics simulations of the TSE are performed with restrictions imposed only on the distances between the pairs of residues with experimentally determined psi of unity. When a site with a fractional psi lies adjacent to a site with psi = 1, the fractional psi generally signifies that the "fractional site" has a distorted geometry in the TSE. When a fractional site is distal to the sites with psi = 1, however, the histidines sample configurations in which the site is absent. The simulations indicate that the psi = 1 sites by themselves can be used to generate a well-defined TSE having near-native topology. values calculated from the TS simulations exhibit mixed agreement with the experimental values. The origin and implication of the disparities are discussed.

SUBMITTER: Baxa MC

PROVIDER: S-EPMC2742336 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Psi-constrained simulations of protein folding transition states: implications for calculating.

Baxa Michael C MC Freed Karl F KF Sosnick Tobin R TR

Journal of molecular biology 20090301 4

Psi-analysis has been used to identify interresidue contacts in the transition state ensemble (TSE) of ubiquitin and other proteins. The magnitude of psi depends on the degree to which an inserted bihistidine (biHis) metal ion binding site is formed in the TSE. A psi equal to zero or one indicates that the biHis site is absent or fully native-like, respectively, while a fractional psi implies that in the TSE, the biHis site recovers only part of the binding-induced stabilization of the native st ...[more]

PMID: 19244613

Similar Datasets

Project description:Characterizing the conformations of protein in the transition state ensemble (TSE) is important for studying protein folding. A promising approach pioneered by Vendruscolo et al. [Nature (London) 409, 641 (2001)] to study TSE is to generate conformations that satisfy all constraints imposed by the experimentally measured φ values that provide information about the native likeness of the transition states. Faísca et al. [J. Chem. Phys. 129, 095108 (2008)] generated conformations of TSE based on the criterion that, starting from a TS conformation, the probabilities of folding and unfolding are about equal through Markov Chain Monte Carlo (MCMC) simulations. In this study, we use the technique of constrained sequential Monte Carlo method [Lin et al., J. Chem. Phys. 129, 094101 (2008); Zhang et al. Proteins 66, 61 (2007)] to generate TSE conformations of acylphosphatase of 98 residues that satisfy the φ-value constraints, as well as the criterion that each conformation has a folding probability of 0.5 by Monte Carlo simulations. We adopt a two stage process and first generate 5000 contact maps satisfying the φ-value constraints. Each contact map is then used to generate 1000 properly weighted conformations. After clustering similar conformations, we obtain a set of properly weighted samples of 4185 candidate clusters. Representative conformation of each of these cluster is then selected and 50 runs of Markov chain Monte Carlo (MCMC) simulation are carried using a regrowth move set. We then select a subset of 1501 conformations that have equal probabilities to fold and to unfold as the set of TSE. These 1501 samples characterize well the distribution of transition state ensemble conformations of acylphosphatase. Compared with previous studies, our approach can access much wider conformational space and can objectively generate conformations that satisfy the φ-value constraints and the criterion of 0.5 folding probability without bias. In contrast to previous studies, our results show that transition state conformations are very diverse and are far from nativelike when measured in cartesian root-mean-square deviation (cRMSD): the average cRMSD between TSE conformations and the native structure is 9.4 Å for this short protein, instead of 6 Å reported in previous studies. In addition, we found that the average fraction of native contacts in the TSE is 0.37, with enrichment in native-like β-sheets and a shortage of long range contacts, suggesting such contacts form at a later stage of folding. We further calculate the first passage time of folding of TSE conformations through calculation of physical time associated with the regrowth moves in MCMC simulation through mapping such moves to a Markovian state model, whose transition time was obtained by Langevin dynamics simulations. Our results indicate that despite the large structural diversity of the TSE, they are characterized by similar folding time. Our approach is general and can be used to study TSE in other macromolecules.

Dataset Information

Psi-constrained simulations of protein folding transition states: implications for calculating.

Publications

Psi-constrained simulations of protein folding transition states: implications for calculating.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets