Multiscale simulations of osmolyte and high-pressure effects on conformational transitions and molecular associations of biomolecular systems

在高压下对复杂的生物分子系统进行建模，对通常用于环境条件的传统方法框架提出了重大挑战。一方面，已建立的模型势函数（所谓的力场）的可靠性尚不清楚。另一方面，高压现象，如调制折叠和缔合热力学和动力学，总是必须在溶剂环境的复杂组成的背景下进行观察。第一个资助期的中心目标是最有效地利用液态积分方程，特别是以三维参考相互作用点模型理论的形式，结合基于经典力场的分子动力学模拟和量子化学，以获得对修改常见力场建模高压环境的需求的清晰视图。根据在这一阶段取得的经验，并与研究股内的伙伴密切合作，制订了似是而非的战略，以加强对力场的描述，目的是减轻可能必须完全重新参数化现有力场所隐含的风险。从第一个资助期得出的结论令人惊讶，因为高压对电子结构的影响可能是实质性的，但与此同时，严格地引导了一种设计策略，以服务于提供健全的高压建模基础设施的长期目标。在建立了简单分子高压力场适应的有效途径，并为重要的渗透液三甲胺- n -氧化物（TMAO）开发了非常精确的力场之后，将利用在前一阶段开发的洞察力和方法进一步取得进展，以解决更广泛的渗透液类别，并建立现实的、一致的相互作用模型，而不仅仅是适用于环境条件的普通力场。要解决的最重要的问题是可变压力条件下电子结构的调制及其对力场优化的影响。原子电荷和扭转力场项将是修改的主要目标，而使用修改模型的分子动力学模拟将立即导致热力学，结构和动力学结果的估计。这些数据将与来自实验伙伴的参考数据进行比较，例如测量的热力学参数、红外和核磁共振光谱量。在基于结构复杂性逐渐增加的系统进行校准后，所得到的力场将用于解决由溶剂化生物分子和渗透物在压力下组成的具体的、实验研究的生物分子系统。

Modeling complex biomolecular systems at high pressure represents a substantial challenge to traditional methodical frameworks typically employed and developed for ambient conditions. On one hand the reliability of established model potential functions (so-called force fields) is unclear. On the other hand, high-pressure phenomena such as modulated folding and association thermodynamics and kinetics always have to be viewed in the context of the complex composition of the solvent environment. The central goal during the first funding period was to make most efficient use of liquid-state integral equation, particularly in the form of the three-dimensional reference interaction site model theory in conjunction with classical force field-based molecular dynamics simulations and quantum chemistry to obtain a clear view on the requirements to modify common force fields for modeling high-pressure environments. Based on the experiences made during this phase, and in close collaboration with partners within the Research Unit, plausible strategies were developed for enhancing force field descriptions with the intention to mitigate risks implied with a potentially necessary complete reparametrization of established force fields. The conclusions drawn from the first funding period were surprising in the sense that high pressure effects on electronic structure can be substantial, but, at the same time, lead stringently to a design strategy for serving the long-term goal of providing a sound high pressure modeling infrastructure. After having established an efficient route for the high-pressure adaption of force fields for simple molecules, and having developed a very accurate force field for the important osmolyte trimethylamine-N-oxide (TMAO), further progress will be made by using the insight and methodology developed during the previous phase to address broader classes of osmolytes and to establish realistic, consistent interaction models beyond common force fields that are suitable for ambient conditions only. The most important issue to address is the modulation of electronic structure under varying pressure conditions and the resulting implications for force field optimization. Atomic charges as well as torsional force field terms will be the primary targets for modification, while molecular dynamics simulations with modified models will immediately lead to an estimate of thermodynamic, structural and kinetic consequences. These will be compared to reference data from experimental partners, such as measured thermodynamic parameters, infrared and nuclear magnetic resonance spectroscopic quantities. After calibration based on systems with gradually increasing structural complexity, the resulting force fields will be employed to address concrete, experimentally investigated biomolecular systems composed of solvated biomolecules and osmolytes under pressure.