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How robust are protein folding simulations with respect to force field parameterization?

ABSTRACT: Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headpiece using four different force fields. In each simulation, we observed a large number of transitions between the unfolded and folded states, and in all four cases, both the rate of folding and the structure of the native state were in good agreement with experiments. We found, however, that the folding mechanism and the properties of the unfolded state depend substantially on the choice of force field. We thus conclude that although it is important to match a single, experimentally determined structure and folding rate, this does not ensure that a given simulation will provide a unique and correct description of the full free-energy surface and the mechanism of folding.

SUBMITTER: Piana S

PROVIDER: S-EPMC3149239 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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How robust are protein folding simulations with respect to force field parameterization?

Piana Stefano S Lindorff-Larsen Kresten K Shaw David E DE

Biophysical journal 20110501 9

Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headpiece using four different force fields. In each simulation, we observed a large number of transitions b ...[more]

PMID: 21539772

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Project description:Membranes are a crucial component of both bacterial and mammalian cells, being involved in signaling, transport, and compartmentalization. This versatility requires a variety of lipid species to tailor the membrane's behavior as needed, increasing the complexity of the system. Molecular dynamics simulations have been successfully applied to study model membranes and their interactions with proteins, elucidating some crucial mechanisms at the atomistic detail and thus complementing experimental techniques. An accurate description of the functional interplay of the diverse membrane components crucially depends on the selected parameters that define the adopted force field. A coherent parameterization for lipids and proteins is therefore needed. In this work, we propose and validate new lipid head group parameters for the GROMOS 54A8 force field, making use of recently published parametrizations for key chemical moieties present in lipids. We make use additionally of a new canonical set of partial charges for lipids, chosen to be consistent with the parameterization of soluble molecules such as proteins. We test the derived parameters on five phosphocholine model bilayers, composed of lipid patches four times larger than the ones used in previous studies, and run 500 ns long simulations of each system. Reproduction of experimental data like area per lipid and deuterium order parameters is good and comparable with previous parameterizations, as well as the description of liquid crystal to gel-phase transition. On the other hand, the orientational behavior of the head groups is more realistic for this new parameter set, and this can be crucial in the description of interactions with other polar molecules. For that reason, we tested the interaction of the antimicrobial peptide lactoferricin with two model membranes showing that the new parameters lead to a weaker peptide-membrane binding and give a more realistic outcome in comparing binding to antimicrobial versus mammal membranes.

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How robust are protein folding simulations with respect to force field parameterization?

Publications

How robust are protein folding simulations with respect to force field parameterization?

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