Modeling structures and transport phenomena of transmembrane channels and transporters

Abstract

Membrane proteins account for more than half of present day drug targets, but an understanding of structure-function relationships in these proteins continues to be a challenge, owing to the difficulties associated with experimental investigations of these proteins. The work in this thesis makes use of all-atom molecular dynamics simulations to address important problems pertaining to membrane proteins. A major problem in drug design targeting membrane proteins is limited availability of experimental structures. Toward this end, an approach has been proposed here for modeling the structures of α-helical membrane proteins. While the approach is able to provide structural models for a number of channel proteins, possible improvements, that would make the approach more suitable for other membrane proteins, are proposed. The other aspect of membrane proteins that has been difficult to investigate experimentally is an atomistic level understanding of the conduction and selectivity mechanism in channels and transporters. This thesis provides insights into the mechanism of transport in a number of channels and transporters, including two viral ion channels, a mammalian aquaporin, and a bacterial urea transporter. While the work on structure modeling reveals some â rulesâ that membrane proteins follow at the time of oligomerization, the studies on transport across membrane proteins suggest that transport proteins have their unique mechanisms for determining selectivity, depending on what chemical species they conduct