title: Design principles for high-pressure force fields: Aqueous TMAO solutions from ambient to kilobar pressures.
abstract: Accurate force fields are one of the major pillars on which successful molecular dynamics simulations of complex biomolecular processes rest. They have been optimized for ambient conditions, whereas high-pressure simulations become increasingly important in pressure perturbation studies, using pressure as an independent thermodynamic variable. Here, we explore the design of non-polarizable force fields tailored to work well in the realm of kilobar pressures--while avoiding complete reparameterization. Our key is to first compute the pressure-induced electronic and structural response of a solute by combining an integral equation approach to include pressure effects on solvent structure with a quantum-chemical treatment of the solute within the embedded cluster reference interaction site model (EC-RISM) framework. Next, the solute's response to compression is taken into account by introducing pressure-dependence into selected parameters of a well-established force field. In our proof-of-principle study, the full machinery is applied to N,N,N-trimethylamine-N-oxide (TMAO) in water being a potent osmolyte that counteracts pressure denaturation. EC-RISM theory is shown to describe well the charge redistribution upon compression of TMAO(aq) to 10 kbar, which is then embodied in force field molecular dynamics by pressure-dependent partial charges. The performance of the high pressure force field is assessed by comparing to experimental and ab initio molecular dynamics data. Beyond its broad usefulness for designing non-polarizable force fields for extreme thermodynamic conditions, a good description of the pressure-response of solutions is highly recommended when constructing and validating polarizable force fields.
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Universität Regensburg, 93040 Regensburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölzl
authors.affiliation: Physikalische Chemie III, Technische Universität Dortmund, 44227 Dortmund, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kibies
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-Universität Bochum, 44780 Bochum, Germany.
authors.forename: Sho
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Physikalische Chemie III, Technische Universität Dortmund, 44227 Dortmund, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Frach
authors.affiliation: Physikalische Chemie I, Technische Universität Dortmund, 44227 Dortmund, Germany.
authors.forename: Saba
authors.initials: S
authors.lastname: Suladze
authors.affiliation: Physikalische Chemie I, Technische Universität Dortmund, 44227 Dortmund, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Winter
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-Universität Bochum, 44780 Bochum, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Marx
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Universität Regensburg, 93040 Regensburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Horinek
authors.affiliation: Physikalische Chemie III, Technische Universität Dortmund, 44227 Dortmund, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Kast
mesh_terms: D008744:Methylamines / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011312:Pressure; D012996:Solutions; D014867:Water / Q000737:chemistry
chemical_list: D008744:Methylamines; D012996:Solutions; D014867:Water; C005855:trimethyloxamine