Understanding Biomolecular Systems ◊ focus on numerical experimentation to probe system behavior at an atomic level ◊ principle software tools: molecular dynamics quantum/classical simulation ◊ provide details unavailable through direct experimentation Research in the Cunningham group focuses on the numerical simulation of physical systems, primarily biomolecular systems. Numerical experimentation can provide details of the atomic interactions that govern biochemical processes and that are often inaccessible to direct experimentation. One example is the self cleavage of the protein backbone of a protein from the bacterium Shewanella oneidensis. The crystal structure of the protein is illustrated, with a clear break in the backbone. http://www.utpa.edu/faculty/cunningham/

Molecular Dynamics ◊ molecular dynamics simulations provide structural information Molecular dynamics simulations start with the protein coordinates taken from the crystal structure. The protein is solvated in a large box of water and then we solve Newton’s equations of motion for ~2 million time steps to analyze the structural behavior of the system. In the movie, we have suppressed everything but the protein backbone to illustrate that proteins in solution are not rigid.

QM/MM simulations ◊ quantum/classical (QM/MM) simulations provide information about energetics along the chemical pathway This animation shows the quantum atoms (~50 in all) in the active site of the protein. The remaining atoms in the model (gray) provide a background electrostatic field for the quantum calculations. The water molecule in the center attacks the protein backbone and severs the bond between the aspartic acid and the proline (5-membered ring) residues.

◊ understanding mechanisms at an atomic level Pro117 ◊ understanding mechanisms at an atomic level ◊ insight into biological function ◊ potential drug targets Asp116 water Our numerical experiments allow us to consolidate disparate experimental data into a coherent framework. By understanding the chemical mechanisms at work in the systems studied, we gain insight into the biological function. For some key biological pathways, the enzymes that we study pose potential drug targets, either through inhibiting or upregulating their function.