TITLE: "Identifying rigid and flexible regions in proteins."

SPEAKER: Professor Donald Jacobs,

TIME: Thursday, January 21, 1999, starting at 4:00 PM

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

The microstructure of a protein is represented as a generic bar-joint truss framework, where hard covalent forces and strong hydrogen bonds are modeled as distance constraints. The mechanical stability is analyzed using graph theoretical techniques with the aid of the FIRST program that determines the Floppy Inclusion and Rigid Substructure Topography. FIRST provides a real-time tool for evaluating intrinsic flexibility in protein structure. Unlike many methods for parsing protein folds, this approach calculates exact mechanical properties of a protein structure (and other macromolecules) under a given set of distance constraints. These properties include; counting the number of independent degrees of freedom associated with floppy modes, locating over-constrained regions where internal strain arises, partitioning the protein structure into rigid clusters and identifying under-constrained regions where continuous deformations can take place. It is shown that the predicted flexibility in HIV protease, agrees well with experimental temperature (Debye-Waller) factors and the inferred flexibility obtained by taking differences in the dihedral angles between two conformational states. These results suggest that hydrogen-bond interactions are not only responsible for forming secondary structures in a protein, but also account for most of the non-covalent constraints determining intrinsic flexibility. The FIRST analysis is also applied to the lysine/arginine/ornithine-binding protein, where it is shown that the rigid cluster partitioning is well conserved between the open and closed conformations, but with some differences that correlate with kinetic measurements.