Are current atomistic force fields accurate enough to study proteins in crowded environments?

The high concentration of macromolecules in the crowded cellular interior influences different thermodynamic and kinetic properties of proteins, including their structural stabilities, intermolecular binding affinities and enzymatic rates. Moreover, various structural biology methods, such as NMR or...

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Autores principales:	Drazen Petrov, Bojan Zagrovic
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7679953f98ed4d5a9d411c383742a757
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spelling	oai:doaj.org-article:7679953f98ed4d5a9d411c383742a7572021-11-11T05:52:09ZAre current atomistic force fields accurate enough to study proteins in crowded environments?1553-734X1553-735810.1371/journal.pcbi.1003638https://doaj.org/article/7679953f98ed4d5a9d411c383742a7572014-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24854339/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The high concentration of macromolecules in the crowded cellular interior influences different thermodynamic and kinetic properties of proteins, including their structural stabilities, intermolecular binding affinities and enzymatic rates. Moreover, various structural biology methods, such as NMR or different spectroscopies, typically involve samples with relatively high protein concentration. Due to large sampling requirements, however, the accuracy of classical molecular dynamics (MD) simulations in capturing protein behavior at high concentration still remains largely untested. Here, we use explicit-solvent MD simulations and a total of 6.4 µs of simulated time to study wild-type (folded) and oxidatively damaged (unfolded) forms of villin headpiece at 6 mM and 9.2 mM protein concentration. We first perform an exhaustive set of simulations with multiple protein molecules in the simulation box using GROMOS 45a3 and 54a7 force fields together with different types of electrostatics treatment and solution ionic strengths. Surprisingly, the two villin headpiece variants exhibit similar aggregation behavior, despite the fact that their estimated aggregation propensities markedly differ. Importantly, regardless of the simulation protocol applied, wild-type villin headpiece consistently aggregates even under conditions at which it is experimentally known to be soluble. We demonstrate that aggregation is accompanied by a large decrease in the total potential energy, with not only hydrophobic, but also polar residues and backbone contributing substantially. The same effect is directly observed for two other major atomistic force fields (AMBER99SB-ILDN and CHARMM22-CMAP) as well as indirectly shown for additional two (AMBER94, OPLS-AAL), and is possibly due to a general overestimation of the potential energy of protein-protein interactions at the expense of water-water and water-protein interactions. Overall, our results suggest that current MD force fields may distort the picture of protein behavior in biologically relevant crowded environments.Drazen PetrovBojan ZagrovicPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 5, p e1003638 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Drazen Petrov Bojan Zagrovic Are current atomistic force fields accurate enough to study proteins in crowded environments?
description	The high concentration of macromolecules in the crowded cellular interior influences different thermodynamic and kinetic properties of proteins, including their structural stabilities, intermolecular binding affinities and enzymatic rates. Moreover, various structural biology methods, such as NMR or different spectroscopies, typically involve samples with relatively high protein concentration. Due to large sampling requirements, however, the accuracy of classical molecular dynamics (MD) simulations in capturing protein behavior at high concentration still remains largely untested. Here, we use explicit-solvent MD simulations and a total of 6.4 µs of simulated time to study wild-type (folded) and oxidatively damaged (unfolded) forms of villin headpiece at 6 mM and 9.2 mM protein concentration. We first perform an exhaustive set of simulations with multiple protein molecules in the simulation box using GROMOS 45a3 and 54a7 force fields together with different types of electrostatics treatment and solution ionic strengths. Surprisingly, the two villin headpiece variants exhibit similar aggregation behavior, despite the fact that their estimated aggregation propensities markedly differ. Importantly, regardless of the simulation protocol applied, wild-type villin headpiece consistently aggregates even under conditions at which it is experimentally known to be soluble. We demonstrate that aggregation is accompanied by a large decrease in the total potential energy, with not only hydrophobic, but also polar residues and backbone contributing substantially. The same effect is directly observed for two other major atomistic force fields (AMBER99SB-ILDN and CHARMM22-CMAP) as well as indirectly shown for additional two (AMBER94, OPLS-AAL), and is possibly due to a general overestimation of the potential energy of protein-protein interactions at the expense of water-water and water-protein interactions. Overall, our results suggest that current MD force fields may distort the picture of protein behavior in biologically relevant crowded environments.
format	article
author	Drazen Petrov Bojan Zagrovic
author_facet	Drazen Petrov Bojan Zagrovic
author_sort	Drazen Petrov
title	Are current atomistic force fields accurate enough to study proteins in crowded environments?
title_short	Are current atomistic force fields accurate enough to study proteins in crowded environments?
title_full	Are current atomistic force fields accurate enough to study proteins in crowded environments?
title_fullStr	Are current atomistic force fields accurate enough to study proteins in crowded environments?
title_full_unstemmed	Are current atomistic force fields accurate enough to study proteins in crowded environments?
title_sort	are current atomistic force fields accurate enough to study proteins in crowded environments?
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/7679953f98ed4d5a9d411c383742a757
work_keys_str_mv	AT drazenpetrov arecurrentatomisticforcefieldsaccurateenoughtostudyproteinsincrowdedenvironments AT bojanzagrovic arecurrentatomisticforcefieldsaccurateenoughtostudyproteinsincrowdedenvironments
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Are current atomistic force fields accurate enough to study proteins in crowded environments?

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