共溶剂排除在三甲胺 N-氧化物和甜菜碱溶液中提高蛋白质稳定性,The Journal of Physical Chemistry Letters

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共溶剂排除在三甲胺 N-氧化物和甜菜碱溶液中提高蛋白质稳定性
The Journal of Physical Chemistry Letters ( IF 4.8 ) Pub Date : 2022-08-19 , DOI: 10.1021/acs.jpclett.2c01692
Pritam Ganguly ₁ , Dominik Bubák ₂ , Jakub Polák ₂ , Patrik Fagan ₃ , Martin Dračínský ₄ , Nico F A van der Vegt ₅ , Jan Heyda ₂ , Joan-Emma Shea _{1,

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Affiliation

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液三甲胺N中的溶剂化热力学-氧化物（TMAO）和甜菜碱。我们表明，现有的力场无法捕捉蛋白质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 - 渗透物相互作用的不准确参数化促进了 trpcage 蛋白的非物理强热变性。我们为甜菜碱开发了一种新颖的力场（KBB 力场），它再现了实验解 Kirkwood-Buff 积分和密度。我们进一步在甜菜碱和 TMAO 力场中对蛋白质-渗透剂相互作用进行了适当的缩放，从而成功复制了溶菌酶和核糖核酸酶 T1 的实验性蛋白质-渗透剂优先结合系数，并防止了渗透剂溶液中 trpcage 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折叠构象的稳定，而未校正的参数使折叠结构不稳定。我们的结果表明，甜菜碱和 TMAO 溶液中蛋白质的热力学稳定性受蛋白质中渗透质排除的控制。

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Cosolvent Exclusion Drives Protein Stability in Trimethylamine N-Oxide and Betaine Solutions

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 N-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.

更新日期：2022-08-19

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