Ganguly Pritam, Polák Jakub, van der Vegt Nico F A, Heyda Jan, Shea Joan-Emma
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, California 93106, United States.
Department of Physical Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
J Phys Chem B. 2020 Jul 23;124(29):6181-6197. doi: 10.1021/acs.jpcb.0c04357. Epub 2020 Jun 25.
Osmolytes are essential for cellular function under ubiquitous osmotic stress. Trimethylamine -oxide (TMAO) is one such osmolyte that has gained remarkable attention due to its protein-protective ability against urea. This Review aims at providing a detailed account of recent theoretical and experimental developments in characterizing the structural changes and thermodynamic stability of proteins in the presence of TMAO and urea. New vapor pressure osmometry and molecular dynamics simulation results on urea-TMAO solutions are presented, and a unified molecular mechanism of TMAO counteraction of urea-induced protein denaturation is introduced. In addition, a detailed technical assessment of molecular dynamics force fields for TMAO and for urea-TMAO solutions is presented. The force field analysis highlights how many of the commonly used force field models are in fact incompatible with solvation thermodynamics and can lead to misleading conclusions. A new optimized force field for TMAO (Shea(m)) is presented, and a recently optimized force field for TMAO-urea (Netz(m)) that best reproduces experimental data is highlighted.
在普遍存在的渗透胁迫下，渗透溶质对细胞功能至关重要。三甲胺氧化物（TMAO）就是这样一种渗透溶质，因其对尿素具有蛋白质保护能力而备受关注。本综述旨在详细介绍近期在表征TMAO和尿素存在下蛋白质的结构变化和热力学稳定性方面的理论和实验进展。给出了关于尿素-TMAO溶液的新蒸气压渗透压测定法和分子动力学模拟结果，并介绍了TMAO对抗尿素诱导蛋白质变性的统一分子机制。此外，还对TMAO以及尿素-TMAO溶液的分子动力学力场进行了详细的技术评估。力场分析突出了许多常用力场模型实际上如何与溶剂化热力学不兼容，并可能导致误导性结论。提出了一种新的TMAO优化力场（Shea(m)），并强调了一种最近优化的、最能重现实验数据的TMAO-尿素力场（Netz(m)）。
