000130773 001__ 130773 000130773 005__ 20240201145618.0 000130773 0247_ $$2doi$$a10.1021/acs.jcim.9b00430 000130773 0248_ $$2sideral$$a114299 000130773 037__ $$aART-2019-114299 000130773 041__ $$aeng 000130773 100__ $$0(orcid)0000-0002-1896-7805$$aGalano-Frutos, Juan José$$uUniversidad de Zaragoza 000130773 245__ $$aAccurate Calculation of Barnase and SNase Folding Energetics Using Short Molecular Dynamics Simulations and an Atomistic Model of the Unfolded Ensemble: Evaluation of Force Fields and Water Models 000130773 260__ $$c2019 000130773 5060_ $$aAccess copy available to the general public$$fUnrestricted 000130773 5203_ $$aAs proteins perform most cellular functions, quantitative understanding of protein energetics is required to gain control of biological phenomena. Accurate models of native proteins can be obtained experimentally, but the lack of equally fine models of unfolded ensembles impedes the calculation of protein folding energetics from first principles. Here, we show that an atomistic unfolded ensemble model, consisting of a few dozen conformations built from a protein sequence, can be used in conjunction with an X-ray structure of its native state to calculate accurately by difference the changes in enthalpy and heat capacity of the polypeptide upon folding. The calculation is done using molecular dynamics simulations, popular force fields, and water models, and for the two model proteins studied (barnase and SNase), the results agree within error or are very close to their experimentally determined properties. The enthalpy sampling of the unfolded ensemble is done through short 2 ns simulations that do not significantly modify the representative distribution of R<inf>g</inf> of the starting conformations. The impressive accuracy obtained opens the possibility to investigate quantitatively systems or phenomena not amenable to experiment and paves the way for addressing the calculation of protein conformational stability (i.e., the change in Gibbs energy upon folding), a central goal of structural biology. So far, these calculated enthalpy and heat capacity changes, combined with the experimentally determined melting temperatures of the corresponding protein, allow us to reproduce the stability curves of both barnase and SNase. 000130773 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P 000130773 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/ 000130773 590__ $$a4.549$$b2019 000130773 591__ $$aCHEMISTRY, MEDICINAL$$b11 / 61 = 0.18$$c2019$$dQ1$$eT1 000130773 591__ $$aCOMPUTER SCIENCE, INFORMATION SYSTEMS$$b28 / 155 = 0.181$$c2019$$dQ1$$eT1 000130773 591__ $$aCOMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS$$b17 / 109 = 0.156$$c2019$$dQ1$$eT1 000130773 592__ $$a1.329$$b2019 000130773 591__ $$aCHEMISTRY, MULTIDISCIPLINARY$$b49 / 176 = 0.278$$c2019$$dQ2$$eT1 000130773 593__ $$aChemical Engineering (miscellaneous)$$c2019$$dQ1 000130773 593__ $$aLibrary and Information Sciences$$c2019$$dQ1 000130773 593__ $$aComputer Science Applications$$c2019$$dQ1 000130773 593__ $$aChemistry (miscellaneous)$$c2019$$dQ1 000130773 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion 000130773 700__ $$0(orcid)0000-0002-2879-9200$$aSancho, Javier$$uUniversidad de Zaragoza 000130773 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000130773 773__ $$g(2019), [11 pp]$$pJ. Chem Inf. Model.$$tJournal of Chemical Information and Modeling$$x1549-9596 000130773 8564_ $$s1680996$$uhttps://zaguan.unizar.es/record/130773/files/texto_completo.pdf$$yPostprint 000130773 8564_ $$s790813$$uhttps://zaguan.unizar.es/record/130773/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint 000130773 909CO $$ooai:zaguan.unizar.es:130773$$particulos$$pdriver 000130773 951__ $$a2024-02-01-14:52:27 000130773 980__ $$aARTICLE