MOLECULAR MODELNG OF COMPLEX BIOLOGICAL SYSTEMS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We are requesting TeraGrid access to enable the continuation of our work on the calculation of free energies and self-assembly in biological systems. In particular, we have two goals: first, to understand the mechanism of action of cellulase enzymes, and, second, to study the self-assembly of skin lipids. In addressing the first goal, we focus on cellobiohydrolase I (CBH1), one of the most active cellulose enzymes known. Therefore, understanding its mechanism of action on cellulose is central to realizing biomass as a viable renewable fuel. CBH1 contains three principal domains - the catalytic domain, binding domain and linker peptide - that function cooperatively to hydrolyze cellulose and liberate glucose, a sugar suitable for many fermentative processes. Although the sequence of the linker peptide is known and it has been shown that the linker plays an important role in enzymatic activity during cellulose hydrolysis, the spatial conformation adopted by the linker domain is yet to be determined. We will probe this through molecular dynamics simulations in which the motion and conformation of the linker in an aqueous environment are monitored. Potential of mean force calculations will be performed to compute the free energy of the linker as a function of linker length. TeraGrid resources will additionally be to address our second goal, the development and testing of atomistic and coarse-grained models in order to study the self-assembly of skin lipids. We aim to understand what lipids required for self-assembly and to determine the structures formed. Experimental studies have shown that in the stratum corneum (the thin, outer layer of the skin), the skin lipids are organized in ordered gel or crystalline phases, unlike the typical liquid crystalline phases of most biological membranes, thus enabling them to function as an effective barrier. The lipid organization can be ascribed to the unique composition of the SC lipids, which is composed of mostly ceramides, free fatty acids and cholesterol. While much is known about the nature of the skin lipids, a detailed picture of the molecular organization of lipids in the SC has not been elucidated.