Computational structural and functional proteomics 285 Chapter # STRUCTURAL DETERMINANTS OF CARDIOTOXINS MEMBRANE BINDING: A MOLECULAR MODELING APPROACH

dynamics SUMMARY Motivations: Because of experimental difficulties with characterization of membrane – protein interactions, development of molecular modeling approaches is a field of especial interest. To understand how the membrane binding occurs on molecular level and what structural features are responsible for the strength of binding, we applied a new algorithm, combining molecular dynamics (MD) simulations in water followed by Monte-Carlo (MC) search in implicit membrane, to particular biological objects – two homologous cardiotoxins (CTs), CTI and CTII, from snake venom. Results: MD simulations of quite structurally rigid molecules of toxins show that CTs differ significantly in structural stability of their loops I and II. In order to assess the mode of membrane binding for different CTs, their NMR- and MD-derived models were futher employed in MC search with implicit membrane. The results obtained reveal the exclusive role of a charged residue in loop II and minor local differences in structure of toxins in their mode of membrane binding. It is proposed that a long-living water molecule found in the loop II of CT I may play a role in regulating the lipid binding mode of CTs