Journal ArticleDOI
Fast empirical pKa prediction by Ewald summation.
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TLDR
An empirical equation is defined that expresses the pK(a) as a function of electrostatic potential, hydrogen bonds and accessible surface area and reaches a high overall jack-knifed accuracy, and is fast enough to be used during a molecular dynamics simulation.Abstract:
pK(a) calculations for macromolecules are normally performed by solving the Poisson-Boltzmann equation, accounting for the different dielectric constants of solvent and solute, as well as the ionic strength. Despite the large number of successful applications, there are some situations where the current algorithms are not suitable: (1) large scale, high-throughput analysis which requires calculations to be completed within a fraction of a second, e.g. when permanently monitoring pK(a) shifts during a molecular dynamics simulation; (2) prediction of pK(a)s in periodic boundaries, e.g. when reconstructing entire protein crystal unit cells from PDB files, including the correct protonation patterns at experimental pH. Such in silico crystals are needed by 'self-parameterizing' molecular dynamics force fields like YASARA YAMBER, that optimize their parameters while energy-minimizing high-resolution protein crystals. To address both problems, we define an empirical equation that expresses the pK(a) as a function of electrostatic potential, hydrogen bonds and accessible surface area. The electrostatic potential is evaluated by Ewald summation, which captures periodic crystal environments and the uncertainty in atom positions using Gaussian charge densities. The empirical proportionality constants are derived from 217 experimentally determined pK(a)s, and despite its simplicity, this pK(a) calculation method reaches a high overall jack-knifed accuracy, and is fast enough to be used during a molecular dynamics simulation. A reliable null-model to judge pK(a) prediction accuracies is also presented.read more
Citations
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Journal ArticleDOI
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel
Hugues Nury,Catherine Van Renterghem,Catherine Van Renterghem,Yun Weng,Alphonso Tran,Marc Baaden,Virginie Dufresne,Virginie Dufresne,Jean-Pierre Changeux,Jean-Pierre Changeux,James M. Sonner,Marc Delarue,Marc Delarue,Pierre-Jean Corringer,Pierre-Jean Corringer +14 more
TL;DR: Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects, and provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs.
Journal ArticleDOI
RAD21 Mutations Cause a Human Cohesinopathy
Matthew A. Deardorff,Matthew A. Deardorff,Jonathan J. Wilde,Melanie Albrecht,Emma Dickinson,Stephanie Tennstedt,Diana Braunholz,Maren Mönnich,Yuqian Yan,Weizhen Xu,María Concepción Gil-Rodríguez,María Concepción Gil-Rodríguez,Dinah Clark,Hakon Hakonarson,Hakon Hakonarson,Sara Halbach,Laura Daniela Michelis,Abhinav Rampuria,Eva Rossier,Stephanie Spranger,Lionel Van Maldergem,Sally Ann Lynch,Gabriele Gillessen-Kaesbach,Hermann-Josef Lüdecke,Robert G. Ramsay,Robert G. Ramsay,Michael J. McKay,Ian D. Krantz,Ian D. Krantz,Huiling Xu,Huiling Xu,Julia A. Horsfield,Frank J. Kaiser +32 more
TL;DR: It is shown that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a "cohesinopathy," and that dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings.
Journal ArticleDOI
PROGRESS IN THE PREDICTION OF pKa VALUES IN PROTEINS
Emil Alexov,Ernest L. Mehler,Nathan A. Baker,António M. Baptista,Yong Huang,Francesca Milletti,Jens Erik Nielsen,Damien Farrell,Tommy Carstensen,Mats H. M. Olsson,Jana Shen,Jim Warwicker,Sarah L. Williams,J. Michael Word +13 more
TL;DR: This article serves as an introduction to the reports submitted by the blind prediction participants that will be published in a special issue of PROTEINS: Structure, Function and Bioinformatics.
Journal ArticleDOI
Dysfunctional nitric oxide signalling increases risk of myocardial infarction
Jeanette Erdmann,Klaus Stark,Ulrike B. Esslinger,Philipp Moritz Rumpf,Doris Koesling,Cor de Wit,Frank J. Kaiser,Diana Braunholz,Anja Medack,Marcus Fischer,Martina E. Zimmermann,Stephanie Tennstedt,Elisabeth Graf,Sebastian H. Eck,Zouhair Aherrahrou,Janja Nahrstaedt,Christina Willenborg,Petra Bruse,Ingrid Braenne,Markus M. Nöthen,Per Hofmann,Peter S. Braund,Evanthia Mergia,Wibke Reinhard,Christof Burgdorf,Stefan Schreiber,Anthony J. Balmforth,Alistair S. Hall,Lars Bertram,Elisabeth Steinhagen-Thiessen,Shu-Chen Li,Winfried März,Muredach P. Reilly,Sekar Kathiresan,Ruth McPherson,Ulrich Walter,Jurg Ott,Nilesh J. Samani,Tim M. Strom,Thomas Meitinger,Christian Hengstenberg,Heribert Schunkert +41 more
TL;DR: Starting with a severely affected family, this work has identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation, and demonstrated in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1- sGC protein content, and impair soluble guanyly l cyclase activity.
Journal ArticleDOI
A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2.
R. Islam,Rimon Parves,Archi Sundar Paul,Nizam Uddin,Sajjadur Rahman,Abdulla Al Mamun,Nayeem Hossain,Ackas Ali,Mohammad A. Halim +8 more
TL;DR: The comprehensive computational and statistical analysis show that these selected phytochemicals can be used as potential inhibitors against the SARS-CoV-2 and ADMET analysis demonstrates that these candidates appear to be safer inhibitors.
References
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