Five molecular models for trimethylamine N-oxide (TMAO) to be used in conjunction with compatible models for liquid water are evaluated by comparison of molecular dynamics (MD) simulation results to experimental data as functions of TMAO molality. The experimental data comprise thermodynamic properties (density, apparent molar volume, and partial molar volume at infinite dilution), transport properties (self-diffusion and shear viscosity), structural properties (radial distribution functions and degree of hydrogen bonding), and dielectric properties (dielectric spectra and static permittivity). The thermodynamic and transport properties turned out to be useful in TMAO model discrimination while the influence of the water model and the TMAO-water interaction are effectively probed through the calculation of dielectric spectra.

The key to nanoscale control of physical, chemical, and biological processes lies in well‐founded models of noncovalent binding. Atomistic simulations probe the free‐energy surface underlying molecular assembly processes in solution. Two examples of noncovalent binding studied by molecular dynamics simulations are discussed, the dimerization of a water‐soluble perylene bisimide derivative in aqueous solution with a focus on the influence of solvent composition on the aggregation strength and the binding of 1‐butanol to α‐cyclodextrin at infinite dilution with the focus on the determination of method‐independent binding free energies.

Free-energy calculations based on molecular simulations provide access to a wide range of thermodynamic properties such as the solubility and partitioning of a molecule in and between various phases. It is demonstrated how molecular dynamics free-energy simulations may be used to obtain the solubilities of primary alcohols and n-alkanes in water and binding affinities of primary alcohols to a-cyclodextrin. The equivalence of two distinct routes to calculate binding free energies is shown leading to the conclusion that host-guest binding affinities may be used to probe the underlying molecular force field.

The origins of different computational artifacts that may occur in the calculation of one-dimensional potentials of mean force (PMF) via umbrella sampling molecular dynamics simulations and manifest as free energy offset between bulk solvent regions are investigated. By systematic studies, three distinct causes are elucidated: (i) an unfortunate choice of reference points for the umbrella distance restraint; (ii) a misfit in probability distributions between bound and unbound umbrella windows in case of multiple binding modes; (iii) artifacts introduced by the free energy estimator. Starting with a fully symmetric model system consisting of methane binding to a cylindrical host, complexity is increased through the introduction of dipolar interactions between the host and the solvent, the host and the guest molecule or between all involved species, respectively. The manifestation of artifacts is illustrated and their origin and prevention is discussed. Finally, the consequences for the calculation of standard binding free enthalpies is illustrated using the complexation of primary alcohols with α-cyclodextrin as an example.

Relative folding free energies for a series of amide-to-ester mutations in the Pin1-WW domain are calculated using molecular dynamics simulations. Special focus is given to the identification and elimination of a simulation-related bias which was observed in previous work (Eichenberger et al. Biochim. Biophys. Acta 2015, 1850, 983) by comparing simulation results obtained with two different starting structures. Subtle local variations in the protein starting structure may lead to substantial deviations in the calculated free-energy changes as a consequence of differences in the sampled ϕ/ψ-dihedral angle distributions of the mutated residue. It is found that the combination of alchemical transformation with Hamiltonian replica exchange for enhanced sampling reduces the starting structure dependence considerably. Compared to previous work, the improved sampling of both the folded and unfolded states also improves the agreement between simulation and experiment.