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Molecular dynamics/order parameter extrapolation for bionanosystem simulations.

ABSTRACT: A multiscale approach, molecular dynamics/order parameter extrapolation (MD/OPX), to the all-atom simulation of large bionanosystems is presented. The approach starts with the introduction of a set of order parameters (OPs) automatically generated with orthogonal polynomials to characterize the nanoscale features of bionanosystems. The OPs are shown to evolve slowly via Newton's equations, and the all-atom multiscale analysis (AMA) developed earlier (Miao and Ortoleva, J Chem Phys 2006, 125, 44901) demonstrates the existence of their stochastic dynamics, which serve as the justification for our MD/OPX approach. In MD/OPX, a short MD run estimates the rate of change of the OPs, which is then used to extrapolate the state of the system over time that is much longer than the 10(-14) second timescale of fast atomic vibrations and collisions. The approach is implemented in NAMD and demonstrated on cowpea chlorotic mottle virus (CCMV) capsid structural transitions (STs). It greatly accelerates the MD code and its underlying all-atom description of the nanosystems enables the use of a universal interatomic force field, avoiding recalibration with each new application as needed for coarse-grained models. The source code of MD/OPX is distributed free of charge at https://simtk.org/home/mdopx and a web portal will be available via http://sysbio.indiana.edu/virusx.

SUBMITTER: Miao Y

PROVIDER: S-EPMC3351762 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Molecular dynamics/order parameter extrapolation for bionanosystem simulations.

Miao Yinglong Y Ortoleva Peter J PJ

Journal of computational chemistry 20090201 3

A multiscale approach, molecular dynamics/order parameter extrapolation (MD/OPX), to the all-atom simulation of large bionanosystems is presented. The approach starts with the introduction of a set of order parameters (OPs) automatically generated with orthogonal polynomials to characterize the nanoscale features of bionanosystems. The OPs are shown to evolve slowly via Newton's equations, and the all-atom multiscale analysis (AMA) developed earlier (Miao and Ortoleva, J Chem Phys 2006, 125, 449 ...[more]

PMID: 18636559

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Project description:For disordered proteins, ligand binding can be a critical event that changes their structural dynamics. The ability to characterize such changes would facilitate the development of drugs designed to stabilize disordered proteins, whose mis-folding is important for a number of pathologies, including neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular dynamics (MD) simulations to characterize the structural changes in disordered proteins that result from ligand binding. We show here that both an ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P, are disordered, yet exhibit structures that are distinct from chemically denatured unfolded states in solution, and that they undergo transitions to a more structured state upon ligand binding. These systems may serve as models for the characterization of ligand-induced disorder-to-order transitions in proteins using structural proteomics approaches. SIGNIFICANCE: In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular-dynamics simulations to characterize the structural changes in disordered proteins that result from ligand binding. The protein-ligand systems studied here (the ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P) may serve as models for understanding ligand-induced disorder-to-order transitions in proteins. Additionally, the structural proteomic techniques demonstrated here are shown to be effective tools for the characterization of disorder-to-order transitions and can be used to facilitate study of other systems in which this class of structural transition can be used for modulating major pathological features of disease, such as the abnormal protein aggregation that occurs with Parkinson's disease and Alzheimer's disease.

Dataset Information

Molecular dynamics/order parameter extrapolation for bionanosystem simulations.

Publications

Molecular dynamics/order parameter extrapolation for bionanosystem simulations.

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