%0 Generic
%9 Undergraduate Thesis
%A Mills, Brandon Michael
%D 2009
%F pittir:7873
%K  allostery; brownian dynamics; conformational change; domain insertion; mechanically induced unfolding; molecular dynamics; molecular sensor; Go model; protein folding
%T Computational Studies of Mutually Exclusive Folding in a Two-Domain Molecular Switch
%U http://d-scholarship-dev.library.pitt.edu/7873/
%X Enzymatic proteins have their activity tightly regulated, often via conformational switching (shape-changing) events which can turn them on or off in a reversible fashion. A change in shape at one location on a protein can induce a change at another location. The Loh Group at SUNY Medical School has engineered a model system for studying such changes in molecular switches by inserting a guest protein (ubiquitin) into a host (barnase). The two protein domains undergo a thermodynamic tug-of-war that is concluded by the mechanically induced unfolding (and deactivation) of one domain. It has been experimentally shown that through changes in environmental conditions or the addition of effector molecules, the unfolded domain can refold by unfolding its competitor. Methodologies for the design of engineered switches may be used to design novel biological sensors and therapeutics.However, it is difficult to obtain structural information for these molecular switches due to their partially unfolded nature. Therefore, we have conducted atomistic and coarse-grained simulations in order to gain structural insight into mutually exclusive folding. To our knowledge, the simulations described in this thesis document are the first at any level of structural detail to show that the folding of one protein domain can drive the unfolding of another.