The GLYCAM lab at the University of Georgia develops the glycan force field for AMBER, one of the most widely used force fields for molecular mechanics simulation of carbohydrates and lipids. The lab utilizes its superior knowledge of carbohydrate modeling to study how the 3D structure and condensed phase dynamics of these molecules relate to their biological function, particularly with respect to infectious disease and immune response.
One such project focuses on the Influenza hemagglutinin glycoprotein, which mediates adhesion of Influenza A to host tissue via binding of host cell receptor glycans. A key difference in human and avian Influenza is the type of receptor glycan the virus recognizes. Human Influenza exhibits specificity for ?2,6-linked glycans, while avian Influenza exhibits specificity for ?2,3-linked glycans. In order for an avian virus to cross the species barrier and efficiently infect humans, it must acquire a hemagglutinin that can recognize and bind to human host tissue via the ?2,6 glycan. One mechanism by which a hemagglutinin can switch specificity is by antigenic drift, or the random mutation that occurs naturally in RNA viruses.
In order to investigate this mechanism, we are performing large-scale molecular dynamics simulations and energy calculations of Influenza hemagglutinin bound to human and avian type receptor glycans to elucidate the structural determinants of specificity and evaluate the effects of mutations. The structural and binding energy data collected via these methods is of great value towards risk assessment and drug design. Plans for an Influenza risk prediction tool that utilizes our energetic analysis, as well as preliminary scaffold models for inhibitor drugs have already been produced from this work. Future directions include further inhibitor development and the application of energy calculations to optimize inhibitors against potential abrogating mutations.
We are using parallel CPU and GPU based supercomputers to perform the substantial molecular dynamics simulations and energy calculations required for this work, making extensive use of the GPU code developed under the SSE Comprehensive Sustained Innovation in Acceleration of Molecular Dynamics Simulation and Analysis on Graphics Processing Units project, which has significantly revolutionized the timescale and scope of our calculations.
GLYCAM: http://www.glycam.org/