Dataset Information

A Comparison of Three Perturbation Molecular Dynamics Methods for Modeling Conformational Transitions.

ABSTRACT: Targeted, steered, and biased molecular dynamics (MD) are widely used methods for studying transition processes of biomolecules. They share the common feature of adding external perturbations along a conformational progress variable to guide the transition in a predefined direction in conformational space, yet differ in how these perturbations are applied. In the present paper, we report a comparison of these three methods on generating transition paths for two different processes: the unfolding of the B domain of protein A and a conformational transition of the catalytic domain of a Src kinase Lyn. Transition pathways were calculated with different simulation parameters including the choice of progress variable and the simulation length or biasing force constant. A comparison of the generated paths based on structural similarity finds that the three perturbation MD methods generate similar transition paths for a given progress variable in most cases. On the other hand, the path depends more strongly on the choice of progress variable used to move the system between the initial and final states. Potentials of mean force (PMF) were calculated starting from unfolding trajectories to estimate the relative probabilities of the paths. A lower PMF was found for the lowest biasing force constant with BMD.

SUBMITTER: Huang H

PROVIDER: S-EPMC2731424 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Comparison of Three Perturbation Molecular Dynamics Methods for Modeling Conformational Transitions.

Huang He H Ozkirimli Elif E Post Carol Beth CB

Journal of chemical theory and computation 20090401 5

Targeted, steered, and biased molecular dynamics (MD) are widely used methods for studying transition processes of biomolecules. They share the common feature of adding external perturbations along a conformational progress variable to guide the transition in a predefined direction in conformational space, yet differ in how these perturbations are applied. In the present paper, we report a comparison of these three methods on generating transition paths for two different processes: the unfolding ...[more]

PMID: 20161143

Similar Datasets

Project description:BACKGROUND:The characteristic of most lipases is the interfacial activation at a lipid interface or in non-polar solvents. Interfacial activation is linked to a large conformational change of a lid, from a closed to an open conformation which makes the active site accessible for substrates. While for many lipases crystal structures of the closed and open conformation have been determined, the pathway of the conformational transition and possible bottlenecks are unknown. Therefore, molecular dynamics simulations of a closed homology model and an open crystal structure of Burkholderia cepacia lipase in water and toluene were performed to investigate the influence of solvents on structure, dynamics, and the conformational transition of the lid. RESULTS:The conformational transition of B. cepacia lipase was dependent on the solvent. In simulations of closed B. cepacia lipase in water no conformational transition was observed, while in three independent simulations of the closed lipase in toluene the lid gradually opened during the first 10-15 ns. The pathway of conformational transition was accessible and a barrier was identified, where a helix prevented the lid from opening to the completely open conformation. The open structure in toluene was stabilized by the formation of hydrogen bonds.In simulations of open lipase in water, the lid closed slowly during 30 ns nearly reaching its position in the closed crystal structure, while a further lid opening compared to the crystal structure was observed in toluene. While the helical structure of the lid was intact during opening in toluene, it partially unfolded upon closing in water. The closing of the lid in water was also observed, when with eight intermediate structures between the closed and the open conformation as derived from the simulations in toluene were taken as starting structures. A hydrophobic beta-hairpin was moving away from the lid in all simulations in water, which was not observed in simulations in toluene. The conformational transition of the lid was not correlated to the motions of the beta-hairpin structure. CONCLUSION:Conformational transitions between the experimentally observed closed and open conformation of the lid were observed by multiple molecular dynamics simulations of B. cepacia lipase. Transitions in both directions occurred without applying restraints or external forces. The opening and closing were driven by the solvent and independent of a bound substrate molecule.

Dataset Information

A Comparison of Three Perturbation Molecular Dynamics Methods for Modeling Conformational Transitions.

Publications

A Comparison of Three Perturbation Molecular Dynamics Methods for Modeling Conformational Transitions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets