Sensitivity of Water Dynamics to Biologically Significant Surfaces of Monomeric Insulin: Role of Topology and Electrostatic Interactions

Abstract

In addition to the biologically active monomer of the protein insulin circulating in human blood, the molecule also exists in dimeric and hexameric forms that are used as storage. The insulin monomer contains two distinct surfaces, namely, the dimer forming surface (DFS) and the hexamer forming surface (HFS), that are specifically designed to facilitate the formation of the dimer and the hexamer, respectively. In order to characterize the structural and dynamical behavior of interfacial water molecules near these two surfaces (DFS and HFS), we performed atomistic molecular dynamics simulations of insulin with explicit water. Dynamical characterization reveals that the structural relaxation of the hydrogen bonds formed between the residues of DFS and the interfacial water molecules is faster than those formed between water and that of the HFS. Furthermore, the residence times of water molecules in the protein hydration layer for both the DFS and HFS are found to be significantly higher than those for some of the other proteins studied so far, such as HP-36 and lysozyme. In particular, we find that more structured water molecules, with higher residence times (∼ 300-500 ps), are present near HFS than those near DFS. A significant slowing down is observed in the decay of associated rotational auto time correlation functions of O-H bond vector of water in the vicinity of HFS. The surface topography and the arrangement of amino acid residues work together to organize the water molecules in the hydration layer in order to provide them with a preferred orientation. HFS having a large polar solvent accessible surface area and a convex extensive nonpolar region, drives the surrounding water molecules to acquire predominantly an outward H-atoms directed, clathrate-like structure. In contrast, near the DFS, the surrounding water molecules acquire an inward H-atoms directed orientation owing to the flat curvature of hydrophobic surface and the interrupted hydrophilic residual alignment. We have followed escape trajectory of several such quasi-bound water molecules from both the surfaces that reveal the significant differences between the two hydration layers.

Hydration water mobility is enhanced around tau amyloid fibers

“…The local protein topology, determined by the protein conformation, has been proposed to be a key, if not the main, feature determining the hydration water dynamics (41)(42)(43)(44). Significant conformational changes in the fuzzy coat have been shown by NMR spectroscopy to accompany tau fiber formation (11); thus a change in water mobility upon fiber formation is expected.…”

Calculating the absolute binding free energy of the insulin dimer in an explicit solvent

“…For instance, two distinct surfaces (the dimer forming surface and the hexamer forming surface) on an insulin monomer are characterized in ref. 44. The role of the conned water molecules to the stability of the insulin hexamer is studied in ref.…”

Hydration shells of proteins probed by depolarized light scattering and dielectric spectroscopy: Orientational structure is significant, positional structure is not

“…Note that the timescales of 100-300 ps have been reported for the lifetimes of hydrogen-bonds of water bound to the protein. 31,32 In contrast, we are dealing here with the average relaxation time of all water molecules in the simulation box, and the results obtained for waters bound to the protein do not apply here.…”