| "Mechanobiology", "Mechano-transduction" and more recently "Mechanochemistry" are emerging as interesting interfaces between biology, chemistry and engineering, dealing with the action of active forces in biology and cellular response to these forces. Forces within the cellular environment not only induce local conformational changes but also lead to a cascade of intermediate changes which gets transmitted to the immediate surroundings. The forces transmitted to the surroundings can either promote or break specific interactions leading further to functional changes. Atomistic simulations can provide an in-depth analysis of these force-induced conformational changes in complex biological systems at the level of a single atom. This thesis represents a study of how forces promote changes in protein conformation to accommodate the applied forces [Dynamic molecular processes mediate cellular mechano-transduction, Nature, 2011]. Using modeling and simulations we specifically aim to shed light on two of these major processes involving conformational transitions under applied force---Force induced thiol-disulphide reaction in Titin and Translocation and simultaneous unfolding of proteins. "Mechano-chemical coupling" or force-coupled chemical reactions are common occurrence in both prokaryotic and eukaryotic cells. Advances in this field have made it possible to induce a chemical reaction by application of external forces in vitro or in vivo at the level of single molecule and study the force response using Force-clamp Spectroscopy. Protein translocation through transmembrane pores are crucial determinants for biomolecular transport and important in developing nanotechnologies to detect and sequence poly-nucleotides and more recently, poly-peptides. The mechanism of protein translocation depends on pore diameter, the magnitude of the driving force and the local structure adjacent to the point of force application. Molecular dynamics simulations of a single translocation event reveal the time-dependent ordering of intermediate structures of the translocating peptide inside the pore at atomic resolution, geared towards an understanding of the parameters required to tune the process to maximum efficiency. |
