IIIT Hyderabad Publications
Modeling Structures and Transport Phenomena of Transmembrane Channels and Transporters
Author: Siladitya Padhi
Report no: IIIT/TH/2016/58
Advisor:U Deva Priyakumar
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. In the first part of the thesis, it is shown that the protein Vpu from human immunodeficiency virus type 1 (HIV-1) exists in a pentameric state, and a structural model for the oligomeric form of the protein is proposed. Free energy calculations performed on the structural model are able to provide a thermodynamic basis for the weak ion channel activity of the protein. In the next part of the thesis, a structure modeling approach is described that attempts to predict the structures of α-helical membrane proteins by minimizing unfavorable contacts. The approach works well for α-helical channels, and can be extended to all α-helical membrane proteins. This is followed by an investigation of ion conduction and selectivity in the p7 channel from hepatitis C virus (HCV). It is shown that a hydrophobic stretch in the channel preferentially allows the singly charged K+ rather than the doubly charged Ca2+ to pass through, and that interionic repulsion is crucial for ion conduction through the pore. Water transport through the human aquaporin AQP2 is then examined, revealing an almost barrierless permeation profile for water transport. The implications of the restriction of water orientation in the middle region of the pore are discussed. Finally, the mechanism of urea transport through the bacterial urea transporter dvUT is studied, and it is shown that permeating urea molecules are able to overcome a hydrophobic barrier arising from the existence of pore-facing phenylalanine residues by forming stacking interactions with these residues. While the work on structure modeling reveals some “rules” 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.
Full thesis: pdf
Centre for Computational Natural Sciences and Bioinformatics
Copyright © 2009 - IIIT Hyderabad. All Rights Reserved.