A Bioinformatics Approach to the Identification of Conserved and Semi-Conserved Water Molecules in Kinase Domain of Hgrk2 Protein - Abstract
Human G protein-coupled receptor kinase 2 (GRK2) is emerging as a critical hub in cell signalling cascades and also acts as a pharmaceutical target for treating cardiovascular diseases. Based on sequence similarity, human GRKs are classified into three subfamilies: GRK1, GRK2, and GRK4. All GRKs have a central catalytic Ser-Thr Kinase domain having a sequence length of ~270 residues. No detailed computational investigation has yet been reported for evaluating the following information about the kinase domain: (i) identifications of conserved and semi-conserved water molecules (ii) characterization, and effect on salt-bridges in the stabilization of kinase domain and its recognition with other domains. Our previous computational investigations on multiple analyses of crystal structures (bound and unbound conformation of G?G?) reveal the presence of seventeen unique water molecules (IW1 to IW17) that are only available either in hGRK2 with G?G? or without G?G? conformation. Moreover, the present computational investigation also indicates four additional water molecules (W18 to W21) located at the kinase domain of the hGRK2 protein with a putative functional role. MD simulation results suggest that above mentioned four crystal water sites are accessible by crystal water molecules in MD simulation and allow entering of these crystal water molecules at their concerning sites. Apparently, the kinase domain is also been stabilized by three salt-bridges via Lys210---Asp212, Lys220---Glu239, and Lys220---Asp335, and it also gets interconnected with RH and AGC domain via the interaction Lys215---Glu523, and Lys228---Asn502 respectively.