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      Comparison of Secondary Structure Formation Using 10 Different Force Fields in Microsecond Molecular Dynamics Simulations

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          Abstract

          We have compared molecular dynamics (MD) simulations of a β-hairpin forming peptide derived from the protein Nrf2 with 10 biomolecular force fields using trajectories of at least 1 μs. The total simulation time was 37.2 μs. Previous studies have shown that different force fields, water models, simulation methods, and parameters can affect simulation outcomes. The MD simulations were done in explicit solvent with a 16-mer Nrf2 β-hairpin forming peptide using Amber ff99SB-ILDN, Amber ff99SB*-ILDN, Amber ff99SB, Amber ff99SB*, Amber ff03, Amber ff03*, GROMOS96 43a1p, GROMOS96 53a6, CHARMM27, and OPLS-AA/L force fields. The effects of charge-groups, terminal capping, and phosphorylation on the peptide folding were also examined. Despite using identical starting structures and simulation parameters, we observed clear differences among the various force fields and even between replicates using the same force field. Our simulations show that the uncapped peptide folds into a native-like β-hairpin structure at 310 K when Amber ff99SB-ILDN, Amber ff99SB*-ILDN, Amber ff99SB, Amber ff99SB*, Amber ff03, Amber ff03*, GROMOS96 43a1p, or GROMOS96 53a6 were used. The CHARMM27 simulations were able to form native hairpins in some of the elevated temperature simulations, while the OPLS-AA/L simulations did not yield native hairpin structures at any temperatures tested. Simulations that used charge-groups or peptide capping groups were not largely different from their uncapped counterparts with single atom charge-groups. On the other hand, phosphorylation of the threonine residue located at the β-turn significantly affected the hairpin formation. To our knowledge, this is the first study comparing such a large set of force fields with respect to β-hairpin folding. Such a comprehensive comparison will offer useful guidance to others conducting similar types of simulations.

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          Rapid planetesimal formation in turbulent circumstellar discs

          The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.
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            Amino acid substitution matrices from protein blocks.

            Methods for alignment of protein sequences typically measure similarity by using a substitution matrix with scores for all possible exchanges of one amino acid with another. The most widely used matrices are based on the Dayhoff model of evolutionary rates. Using a different approach, we have derived substitution matrices from about 2000 blocks of aligned sequence segments characterizing more than 500 groups of related proteins. This led to marked improvements in alignments and in searches using queries from each of the groups.
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              Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm.

              A major challenge in the post-genome era will be determination of the functions of the encoded protein sequences. Since it is generally assumed that the function of a protein is closely linked to its three-dimensional structure, prediction or experimental determination of the library of protein structures is a matter of high priority. However, a large proportion of gene sequences appear to code not for folded, globular proteins, but for long stretches of amino acids that are likely to be either unfolded in solution or adopt non-globular structures of unknown conformation. Characterization of the conformational propensities and function of the non-globular protein sequences represents a major challenge. The high proportion of these sequences in the genomes of all organisms studied to date argues for important, as yet unknown functions, since there could be no other reason for their persistence throughout evolution. Clearly the assumption that a folded three-dimensional structure is necessary for function needs to be re-examined. Although the functions of many proteins are directly related to their three-dimensional structures, numerous proteins that lack intrinsic globular structure under physiological conditions have now been recognized. Such proteins are frequently involved in some of the most important regulatory functions in the cell, and the lack of intrinsic structure in many cases is relieved when the protein binds to its target molecule. The intrinsic lack of structure can confer functional advantages on a protein, including the ability to bind to several different targets. It also allows precise control over the thermodynamics of the binding process and provides a simple mechanism for inducibility by phosphorylation or through interaction with other components of the cellular machinery. Numerous examples of domains that are unstructured in solution but which become structured upon binding to the target have been noted in the areas of cell cycle control and both transcriptional and translational regulation, and unstructured domains are present in proteins that are targeted for rapid destruction. Since such proteins participate in critical cellular control mechanisms, it appears likely that their rapid turnover, aided by their unstructured nature in the unbound state, provides a level of control that allows rapid and accurate responses of the cell to changing environmental conditions. Copyright 1999 Academic Press.
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                Author and article information

                Journal
                J Chem Theory Comput
                J Chem Theory Comput
                ct
                jctcce
                Journal of Chemical Theory and Computation
                American Chemical Society
                1549-9618
                1549-9626
                19 June 2012
                14 August 2012
                : 8
                : 8
                : 2725-2740
                Affiliations
                []Department of Biochemistry, 1151 Richmond Street North, simpleThe University of Western Ontario , London, Ontario N6A 5C1, Canada
                []Department of Chemistry, 200 University Avenue West, simpleUniversity of Waterloo , Waterloo, Ontario N2L 3G1, Canada
                Author notes
                Article
                10.1021/ct300323g
                3419458
                22904695
                1f40a2fd-135e-4d15-9cf1-a1e2223e9909
                Copyright © 2012 American Chemical Society

                This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.

                History
                : 24 April 2012
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                Custom metadata
                ct300323g
                ct-2012-00323g

                Computational chemistry & Modeling
                Computational chemistry & Modeling

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