Molecular recognition and packing frustration in a helical protein
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Molecular recognition and packing frustration in a helical protein
>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein cal proisn PtoS Comput B«)i 13(12): e1005909.ittps:,'.'joi.r.fg1'10.1371^ojmi. pcòi1005SÚ9Editor. Tobin Rơ/ Sosnek. University of Cncago. UNITED STATESReceived: August 17.2017Accepted: November 28.2017Published Deamồer 19,2017Copjnght: a 2017 Huynh et al. Ths IS an open access ancle dskihuted under Molecular recognition and packing frustration in a helical protein the terms 01 the Creit M Commons Attribution License, which permits unrestricted use, ỡstribution. and reproflixton in any iredim. provided the orọnalMolecular recognition and packing frustration in a helical protein
author and source are credted.Data Availability statement All relevant data are within th= paper and Its Supporting nformaton ties.Funding: Ths woik >PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein operating Grants MOP-84281 to HSC. and a postdoctoral felowshp for LH from the CIHR Tranng Program 'Protein Folding and Interaction Dynamos: Prncpes and Diseases' at the Unversrty of Toronto We are grateful for ths support and theRESEARCH ARTICLEMolecular recognition and packing frustration in a hel Molecular recognition and packing frustration in a helical protein ical proteinLoan Huynh1, Chris Neale2, Regis Pomes’-3*, Hue Sun Chan1'4*1 Department of Biochemistry. University of Toronto, Toronto. Ontario, Canada,Molecular recognition and packing frustration in a helical protein
2 Department of physics, Applied Physics, and Astronomy, Rensselaer Polytechnic Institute. Troy, New York. United Stales of America. 3 Molecular Medi>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein hanWarrhenus.med.toronto.edu (HSC); pomes® sickkids.c-a (Rp)AbstractBiomofecular recognition entails attractive forces for the functional native states and discrimination against potential nonnative interactions that favor alternate stable configurations. The challenge posed by the competition of no Molecular recognition and packing frustration in a helical protein nnative stabilization against native-centric forces is conceptualized as frustration. Experiment indicates that frustration is often minimal in evolveMolecular recognition and packing frustration in a helical protein
d biological systems although nonnative possibilities are intuitively abundant Much of the physical basis of minimal frustration in protein folding th>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein sus native interactions, we compute free energies of association of various combinations of the four helices in Im9 (referred to as HI, H2, H3, and H4) by extensive explicit-water molecular dynamics simulations (total simulated time > 300 ps). focusing primarily on the pairs with the largest native Molecular recognition and packing frustration in a helical protein contact surfaces. H1-H2 and H1-H4 Frustration is detected in H1-H2 packing in that a nonnative packing orientation is significantly stabilized relativMolecular recognition and packing frustration in a helical protein
e to native, whereas such a prominent nonnative effect is not observed for H1-H4 packing. However, in contrast to the favored nonnative H1-H2 packing >PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein ntextual nature of molecular recognition, and suggest further that nonnative effects in H1-H2 packing may be largely avoided by the experimentally inferred Im9 folding transition state with native packing most developed at the H1-H4 rather than the H1-H2 interfaceAuthor summaryBiomolecules need to r Molecular recognition and packing frustration in a helical protein ecognize one another with high specificity: promoting “native" functional intcrmolccular binding events while avoiding detrimental “nonnative" bound cMolecular recognition and packing frustration in a helical protein
onfigurations; i.e., "frustration" the tendency for normative interactions has to be minimized. Folding of globular proteins entails a similar discrim>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein rations by atomic simulations, discovering that partial packing of the lm9 core is frustrated. This frustration is overcome when the entire core ofPtos Computational Biology I httDS ,,7doi.org/10 1371Aournat DCbi. 1005909 December 19.201744951Helix-beltx pacing frustration n bacterial immunity prete Molecular recognition and packing frustration in a helical protein xt lm9>PLOS biologyATIONAL• •computng resources generously prodded by SciNet of Compute Canada ire funders had no rote in study design, data coiecticoMolecular recognition and packing frustration in a helical protein
and analysis. ỚKison to pUrtsh. or preparation (X me manuscnpt.Competing interests: Th* authors have (fcclared that no competing interests east.the p>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein le, contextual aspect of bio molecular recognition and provides a general approach to characterize folding frustration.IntroductionMolecular recognition is the basis of biological function. For different parts of the same molecule or different molecules to recognize one another, a target set of inte Molecular recognition and packing frustration in a helical protein ractions need to be favored while other potential interactions arc disfavored. Biomolecules accomplish these simultaneous tasks via the heterogeneousMolecular recognition and packing frustration in a helical protein
interactions encoded by their sequences. For pro tcins, such energetic heterogeneity is enabled but also constrained by a finite alphabet of twenty am>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein interactions, referred to as frustration, arc often present in biological systems. From a physical standpoint, it is almost certain that some of the frustration is a manifestation of the fundamental molecular constraint on adaptation, although under certain circumstances frustration can be exploited Molecular recognition and packing frustration in a helical protein to serve biological function 13,4|.Protein folding entails intramolecular recognition. Early simulations suggested that normative contacts can be comMolecular recognition and packing frustration in a helical protein
mon during folding [5], This predicted behavior applies particularly to models embodying a simple notion of hydrophobicity as the main driving force |>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein frustration from nonna-live interactions in the form of kinetic traps |9|. Celebrated by the consistency principle (to] and the principle of minimal frustration (11 ]. these empirical trends have inspired Gõ-like modeling, wherein native-centric interactions are used in lieu of a physics based tran Molecular recognition and packing frustration in a helical protein sferable potential 112-14). Extensions of this approach allow nonnative interactions to be treated as perturbations in a largely native-centric framewMolecular recognition and packing frustration in a helical protein
ork [15-17]. rhe success of these models poses a fundamental challenge to our physical understanding as to why, rather non intuitively, natural protei>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein at coarsegrained protein models incorporating rudimentary desolvation barriers exhibit less frustration and higher folding cooperativity than models lacking dcsolvation barriers |7, 19. 20). More recently, and most notably, folding of several small proteins has been achieved in molecular dynamics st Molecular recognition and packing frustration in a helical protein udies with explicit water [21,22|. Nonnative contacts are not significantly populated within sections of the simulated trajectories identified as foldMolecular recognition and packing frustration in a helical protein
ing transition paths [23] though they do impede conformational diffusion [24]. These advances suggest that certain important aspects of protein physic>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein experimentally 122,25-28).In this context, it is instructive to ascertain how atomic force fields, as they stand, disfavor nonnative interactions, so as to help decipher molecular recognition mechanisms in real pro leins. Wc take a step toward this goal by comparing the stabilities of native and no Molecular recognition and packing frustration in a helical protein nnative configurations of fully formed helices from a natural protein. By construction, this approach covers only a fraction of all possible nonnativeMolecular recognition and packing frustration in a helical protein
configurations and therefore only provides, albeit not unimportantly, a lower bound on the full extent of frustration. Nonetheless, because of its fo>PLOS BIOLOGYATIONALCheck for updatesâ OPEN ACCESSCitation: Hơ/Hh L. Nsale c. Pom* R. Chan HS (2017) MoecuUr iwogntonand packing frustration in a helc Molecular recognition and packing frustration in a helical protein 05909 December 19.201744982Ỉ3PLOS• •Gọi ngay
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