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

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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.