Interactions of drugs with membranes; implications for off-target effects on membrane protein function
09 / 2011 - onbekend
This proposal aims to quantify the modulation of membrane protein function by drug-induced changes in bilayer properties. There exists an enormous quantity of experimental results on the ?membrane regulation? of membrane protein function. These results have been approximated using various continuum descriptions but there is a pressing need to develop detailed models of membrane protein-lipid bilayer interactions?models that include interfacial interactions, lipid/amphiphile lateral rearrangements and explicit inclusion of the proteins? shape. I therefore propose to develop multi-scale molecular dynamics simulation systems composed of a membrane protein in bilayers of different lipid and amphiphile composition and define descriptors for the protein-bilayer coupling. The project will be incremental, starting with simple lipid systems and a model protein, then iteratively varying the bilayer and later the protein, in each step comparing our predictions with experimental data through collaboration with Prof. Olaf Andersen (Weill Cornell) and Prof. Armağan Koçer (University of Groningen). To meet the requirement of repeated simulations, for statistical significance, and long simulations, for examining lateral rearrangement, I will do coarse-grained simulations using the host group?s, MARTINI force field. Resolving protein-bilayer interfacial interactions requires full atomistic simulations, which can be included using the host group?s newly developed multi-scale simulation methodologies.