Atomistic simulation study of the coupled motion of amino acid residues and water molecules around protein HP-36: Fluctuations at and around the active sites

The chicken villin headpiece subdomain, popularly known as HP-36, is an actin binding protein. It consists of 36 amino acid residues in three alpha-helices and four coils. The biological activity of the protein is found to be centered around helix-3, which contains 10 amino acid residues. We have performed atomistic molecular dynamics simulations of HP-36 with explicit water in order to investigate the correlation, if any, between the dynamics of the amino acid residues, dynamics of surrounding water molecules, and the biological activity of the protein. We calculate the time trajectory of the root mean square deviation (RMSD) of individual amino acid residues, the rotational and translational motion of water molecules, and the dynamics of hydrogen bonds formed between the protein residues and the interfacial water molecules near different segments of HP-36. We find that the amino acid residues in the short helices 1 and 2 exhibit no interesting dynamics; the time trajectory of their RMSD shows only minor changes with time. In contrast, the residues in helix-3 (the biologically active one) show highly interesting dynamics, often exhibiting large amplitude, sometimes nearly oscillatory motions. Simultaneously, the water molecules near helix-3 are found to exhibit noticeably faster rotational and translational motions. It has been observed that the structural relaxation of the hydrogen bonds formed between the residues in helix-3 and the interfacial water molecules is faster than that for the other two helices. Analysis of the structural arrangement of water molecules around the protein in terms of the radial distribution function shows that not only are there fewer water molecules around helix-3 but they are also less structured than those around helices 1 and 2. This is somewhat surprising because the third helix contains several hydrophilic groups. Analysis of the structure of the protein shows that few polar hydrophilic residues remain buried within the core of the protein, which partly explains the lack of structure of water molecules around helix-3.