Protein-water interactions studied by molecular dynamics simulations

Most proteins have evolved to function optimally in aqueous environments, and the interactions between protein and water therefore play a fundamental role in the stability, dynamics, and function of proteins. Although we understand many details of water, we understand much less about the protein-water interface. In this thesis we use molecular dynamics (MD) simulations to cast light on many structural and dynamical properties of protein hydration for which a detailed picture is lacking.

We show that the 1 ms MD simulation of the bovine pancreatic trypsin inhibitor (BPTI) by Shaw \textsl{et al.} (Science 2010, 330, 341) reproduces the mean survival times from magnetic relaxation dispersion (MRD) experiments by computing the relevant survival correlation function that is probed by these experiments. The simulation validates several assumptions in the model used to interpret MRD data, and reveals a possible mechanism for the water-exchange; water molecules gain access to the internal sites by a transient aqueduct mechanism, migrating as single-file water chains through transient tunnels or pores. The same simulation was also used to reveal a possible mechanism for hydrogen exchange of backbone amides, involving short-lived locally distorted conformations of the protein whereby the amide is presolvated by two water molecules before the catalyst can approach the amide through a water wire.

We perform MD simulations of several small globular proteins in dilute aqueous solution to spatially resolve protein hydration. Defining mono-molecular thick hydration shells as a metric from the protein surface, we compute structural and dynamical properties of water in these shells and show that the protein-induced water perturbation is short ranged, essentially only affecting water molecules in the first hydration shell, thus validating the model used to interpret MRD data. Compared to the bulk, the first shell is 6 \% more dense and 25-30 \% less compressible. The shell-averaged rotation of water molecules in the first hydration shell is retarded by a factor 4-5 compared to bulk, and the contributions to this retardation can be resolved based on a universal confinement index. The dynamical heterogeneity in the first shell is a result of water molecules rotating by different mechanisms on a spectrum between two extremes: a collective bulk-like mechanism and a protein-coupled mechanism where water molecules in confined sites are orientationally restricted and require an exchange event.