In this dissertation, we have developed novel computational techniques that have been effectively utilized to extend our knowledge of proteins and lipid membrane systems. Application of molecular dynamics combined with newly developed techniques and protocols to study protein structure refinement and interactions of amino-acid analog pairs within lipid membranes are studied. A robust protocol for structure refinement of proteins from a given homologous model is designed and optimized that uses restrained molecular dynamics followed by optimal subset selection and structure averaging. This protocol is tested on CASP8 and CASP9 targets, and later successfully applied to CASP10 in blind prediction manner.In order to understand physical characteristics of peptide interactions embedded in bilayer membrane, we have used umbrella sampling technique with model amino acid side-chain analog pairs to study their association free energy while placed in membrane bilayer. As a result of convergence issues observed in such simulations due to bilayer deformation, a novel enhanced sampling technique is developed which biases the density of water in a cylinder, thereby effectively imposing bilayer deformation. Applying this method to a DPPC bilayer, we were able to study free energy of pore formation in membrane bilayers, and showed that while the undergone mechanism is different from currently existing methods, the mechanism by our proposed method is closer to the natural pore formation mechanism.
Read
