WFU Physics Colloquium

TITLE: Modeling Protein Stability Using Constraint Theory: Addressing Non-additivity of Entropy in Free Energy Decomposition Schemes

SPEAKER: Professor Donald J. Jacobs ,

TIME: Thursday Nov. 15, 2007 at 4:00 PM

PLACE: George P. Williams, Jr. Lecture Hall, (Olin 101)

Proteins are large macromolecules consisting of many noncovalent interactions that determine their three-dimensional structure and stability. Manipulating protein stability and/or function is desired in protein engineering and the pharmaceutical industry. The importance of conformational flexibility to function is well known. For example, enzymes must be flexible enough to mediate a reaction pathway, yet rigid enough to achieve molecular recognition. Consequently, conformational flexibility is a critical link between structure, stability and function. A difficult challenge in biophysical modeling is to develop methods that accurately predict protein flexibility and stability under given thermodynamic and solvent conditions in computing times fast enough for high throughput computational biology applications. I will discuss a promising new paradigm that combines constraint theory with free energy decomposition schemes. Merging these two concepts leads to a Distance Constraint Model (DCM) that is computationally tractable using fast graph-rigidity algorithms. Computational results are presented on the folding/unfolding transitions in the beta hairpin turn and in proteins using mean field approximations. Lastly, I will discuss our recent results for solving the DCM using an ab initio approach that directly works with classical configuration integrals. This work is supported by NIH in a collaborative effort with Dennis Livesay, Department of Computer Science and Bioinformatics Research Center at UNC Charlotte.