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为环境条件采用和开发的传统方法框架提出了实质性挑战。一方面，所建立的模型势函数（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来看待。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位点模型理论的形式，结合基于经典力场的分子动力学模拟和量子化学，以明确修改高压环境建模的常见力场的要求。根据这一阶段取得的经验，并与研究股内的伙伴密切合作，制定了合理的战略，以加强力场描述，目的是减轻可能需要对现有力场进行完全重新参数化所带来的风险。从第一个资助期得出的结论是令人惊讶的，在这个意义上，高压对电子结构的影响可能是巨大的，但与此同时，严格地导致一个设计策略，为提供一个健全的高压建模基础设施的长期目标服务。在为简单分子的高压力场适应建立了一条有效的路线，并为重要的渗透剂三甲胺-N-氧化物（TMAO）开发了一个非常精确的力场之后，将通过使用前一阶段开发的见解和方法来解决更广泛的渗透剂类别并建立现实的，一致的相互作用模型，超越了共同的力场，只适合于环境条件。要解决的最重要的问题是在不同的压力条件下的电子结构的调制和力场优化所产生的影响。原子电荷以及扭转力场项将是修改的主要目标，而修改后的模型的分子动力学模拟将立即导致热力学，结构和动力学后果的估计。这些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。在基于具有逐渐增加的结构复杂性的系统进行校准之后，所产生的力场将用于解决由溶剂化生物分子和渗透剂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.