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Protein structure refinement of CASP target proteins using GNEIMO torsional dynamics method.

ABSTRACT: A longstanding challenge in using computational methods for protein structure prediction is the refinement of low-resolution structural models derived from comparative modeling methods into highly accurate atomistic models useful for detailed structural studies. Previously, we have developed and demonstrated the utility of the internal coordinate molecular dynamics (MD) technique, generalized Newton-Euler inverse mass operator (GNEIMO), for refinement of small proteins. Using GNEIMO, the high-frequency degrees of freedom are frozen and the protein is modeled as a collection of rigid clusters connected by torsional hinges. This physical model allows larger integration time steps and focuses the conformational search in the low frequency torsional degrees of freedom. Here, we have applied GNEIMO with temperature replica exchange to refine low-resolution protein models of 30 proteins taken from the continuous assessment of structure prediction (CASP) competition. We have shown that GNEIMO torsional MD method leads to refinement of up to 1.3 Å in the root-mean-square deviation in coordinates for 30 CASP target proteins without using any experimental data as restraints in performing the GNEIMO simulations. This is in contrast with the unconstrained all-atom Cartesian MD method performed under the same conditions, where refinement requires the use of restraints during the simulations.

SUBMITTER: Larsen AB

PROVIDER: S-EPMC3985798 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Protein structure refinement of CASP target proteins using GNEIMO torsional dynamics method.

Larsen Adrien B AB Wagner Jeffrey R JR Jain Abhinandan A Vaidehi Nagarajan N

Journal of chemical information and modeling 20140116 2

A longstanding challenge in using computational methods for protein structure prediction is the refinement of low-resolution structural models derived from comparative modeling methods into highly accurate atomistic models useful for detailed structural studies. Previously, we have developed and demonstrated the utility of the internal coordinate molecular dynamics (MD) technique, generalized Newton-Euler inverse mass operator (GNEIMO), for refinement of small proteins. Using GNEIMO, the high-fr ...[more]

PMID: 24397429

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Project description:All-atom molecular dynamics simulations are widely used to study the flexibility of protein conformations. However, enhanced sampling techniques are required for simulating protein dynamics that occur on the millisecond timescale. In this work, we show that torsional molecular dynamics simulations enhance protein conformational sampling by performing conformational search in the low-frequency torsional degrees of freedom. In this article, we use our recently developed torsional-dynamics method called Generalized Newton-Euler Inverse Mass Operator (GNEIMO) to study the conformational dynamics of four proteins. We investigate the use of the GNEIMO method in simulations of the conformationally flexible proteins fasciculin and calmodulin, as well as the less flexible crambin and bovine pancreatic trypsin inhibitor. For the latter two proteins, the GNEIMO simulations with an implicit-solvent model reproduced the average protein structural fluctuations and sample conformations similar to those from Cartesian simulations with explicit solvent. The application of GNEIMO with replica exchange to the study of fasciculin conformational dynamics produced sampling of two of this protein's experimentally established conformational substates. Conformational transition of calmodulin from the Ca(2+)-bound to the Ca(2+)-free conformation occurred readily with GNEIMO simulations. Moreover, the GNEIMO method generated an ensemble of conformations that satisfy about half of both short- and long-range interresidue distances obtained from NMR structures of holo to apo transitions in calmodulin. Although unconstrained all-atom Cartesian simulations have failed to sample transitions between the substates of fasciculin and calmodulin, GNEIMO simulations show the transitions in both systems. The relatively short simulation times required to capture these long-timescale conformational dynamics indicate that GNEIMO is a promising molecular-dynamics technique for studying domain motion in proteins.

Dataset Information

Protein structure refinement of CASP target proteins using GNEIMO torsional dynamics method.

Publications

Protein structure refinement of CASP target proteins using GNEIMO torsional dynamics method.

Similar Datasets

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