Solvation free energy arithmetic for small organic molecules.

Solvent-mediated interactions contribute to ligand binding affinities in computational drug design and provide a challenge for theoretical predictions. In this study, we analyze the solvation free energy of benzene derivatives in water to guide the development of predictive models for solvation free energies and solvent-mediated interactions. We use a spatially resolved analysis of local solvation free energy contributions and define solvation free energy arithmetic, which enable us to construct additive models to describe the solvation of complex compounds.

Pressure Effects on Protein Hydration Water Thermodynamics.

In this molecular dynamics simulation study, we analyze the impact of increasing hydrostatic pressure on the solvation of protein surfaces. Apart from the increasing volume work required for the formation of the protein solute cavity at high hydrostatic pressures, no significant additional trend is observed for solvation free energy contributions due to the protein-water interactions analyzed here. The latter is the result of approximately canceling pressure-induced changes of enthalpic and entropic solvation free energy contributions, which can be traced back to changes in the hydration of hydrophilic and hydrophobic groups of the protein.

Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases.

We analyze the role of solvation for enzymatic catalysis in two distinct, artificially designed Kemp Eliminases, KE07 and KE70, and mutated variants that were optimized by laboratory directed evolution. Using a spatially resolved analysis of hydration patterns, intermolecular vibrations, and local solvent entropies, we identify distinct classes of hydration water and follow their changes upon substrate binding and transition state formation for the designed KE07 and KE70 enzymes and their evolved variants. We observe that differences in hydration of the enzymatic systems are concentrated in the active site and undergo significant changes during substrate recruitment.

Signatures of Solvation Thermodynamics in Spectra of Intermolecular Vibrations.

This study explores the thermodynamic and vibrational properties of water in the three-dimensional environment of solvated ions and small molecules using molecular simulations. The spectrum of intermolecular vibrations in liquid solvents provides detailed information on the shape of the local potential energy surface, which in turn determines local thermodynamic properties such as the entropy. Here, we extract this information using a spatially resolved extension of the two-phase thermodynamics method to estimate hydration water entropies based on the local vibrational density of states (3D-2PT).

Distinct Protein Hydration Water Species Defined by Spatially Resolved Spectra of Intermolecular Vibrations.

In this molecular dynamics simulation study, we analyze intermolecular vibrations in the hydration shell of a solvated enyzme, the membrane type 1-matrix metalloproteinase, with high spatial resolution. Our approach allows us to characterize vibrational signatures of the local hydrogen bond network, the translational mobility of water molecules, as well as the molecular entropy, in specific local environments. Our study demonstrates the heterogeneity of water properties within the hydration shell of a complex biomolecule.