Ganguly Pritam, Bubák Dominik, Polák Jakub, Fagan Patrik, Dračínský Martin, van der Vegt Nico F A, Heyda Jan, Shea Joan-Emma
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, California93106, United States.
Department of Physical Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28Prague 6, Czech Republic.
J Phys Chem Lett. 2022 Sep 1;13(34):7980-7986. doi: 10.1021/acs.jpclett.2c01692. Epub 2022 Aug 19.
Using a combination of molecular dynamics simulation, dialysis experiments, and electronic circular dichroism measurements, we studied the solvation thermodynamics of proteins in two osmolyte solutions, trimethylamine -oxide (TMAO) and betaine. We showed that existing force fields are unable to capture the solvation properties of the proteins lysozyme and ribonuclease T1 and that the inaccurate parametrization of protein-osmolyte interactions in these force fields promoted an unphysical strong thermal denaturation of the trpcage protein. We developed a novel force field for betaine (the KBB force field) which reproduces the experimental solution Kirkwood-Buff integrals and density. We further introduced appropriate scaling to protein-osmolyte interactions in both the betaine and TMAO force fields which led to successful reproduction of experimental protein-osmolyte preferential binding coefficients for lysozyme and ribonuclease T1 and prevention of the unphysical denaturation of trpcage in osmolyte solutions. Correct parametrization of protein-TMAO interactions also led to the stabilization of the collapsed conformations of a disordered elastin-like peptide, while the uncorrected parameters destabilized the collapsed structures. Our results establish that the thermodynamic stability of proteins in both betaine and TMAO solutions is governed by osmolyte exclusion from proteins.
我们结合分子动力学模拟、透析实验和电子圆二色性测量，研究了蛋白质在两种渗透溶质溶液（三甲胺氧化物（TMAO）和甜菜碱）中的溶剂化热力学。我们发现现有的力场无法捕捉溶菌酶和核糖核酸酶T1的溶剂化特性，并且这些力场中蛋白质 - 渗透溶质相互作用的参数化不准确，导致了trpcage蛋白出现非物理性的强烈热变性。我们开发了一种用于甜菜碱的新型力场（KBB力场），它能重现实验性的溶液柯克伍德 - 布夫积分和密度。我们还对甜菜碱和TMAO力场中的蛋白质 - 渗透溶质相互作用引入了适当的标度，这成功重现了溶菌酶和核糖核酸酶T1的实验性蛋白质 - 渗透溶质优先结合系数，并防止了trpcage在渗透溶质溶液中的非物理变性。蛋白质 - TMAO相互作用的正确参数化也导致了无序弹性蛋白样肽的折叠构象的稳定，而未校正的参数则使折叠结构不稳定。我们的结果表明，蛋白质在甜菜碱和TMAO溶液中的热力学稳定性受蛋白质对渗透溶质的排斥作用支配。
