Book of Abstracts: Albany 2003
June 17-21 2003
Inferring Large-scale Motions and Functions from Structures
By representing proteins as a coarse-grained uniform block of material, utilizing only one representative point per residue and connecting the close residues to one another with identical springs, the normal modes of motion can be obtained. Because of the coarse graining, the largest scale motions, which are the most important, should be the most reliable. These are motions of proteins that are not readily accessible by other computational methods. The analysis involves inversion of the contact matrix that specifies the residues connected by springs. We have now applied this approach to a number of proteins and are able to observe motions that characterize functional aspects of proteins.
HIV Reverse Transcriptase
A combination of these slow motions are likely to be involved in the processing step, where the RNA or DNA strand is copied onto a new DNA strand at a polymerase site, and the RNA strand is subsequently cut up at the distant Ribonuclease H site. The slowest mode of motion involves hinge bending about a site midway between the polymerase and Ribonuclease H sites, suggesting that it can push or pull the RNA strand between these two sites. Pulling the nucleic acid strand through the polymerase site would require tight binding at the RNase H site. The next slowest mode involves opening and closing the protein like a clamp, which would facilitate the release of the nucleic acid strand for its step-wise progression. The third mode could rotate the nucleic acid strand. An overall mechanism of the step-wise processing step would involve coordination of these motions.
This approach has also been applied to the GroEL/GroES chaperonin complex. In this case extremely diverse motions are seen, many of which exhibit cylindical symmetry. Notable among these are squeezing motions, elongation and compression along the cylinder axis, wobbling of the GroES head, and screw motions of the cis and trans rings in opposing directions. We have investigated changes to the cavity for these motions, in terms of both volume and hydrophobicity changes.
A remarkable increase in cooperativity is observed upon dimer formation. The principal slowest motions are wobbles at the subunit-subunit interface and stretching along the long axis of the dimer. New approximations have been developed that now will permit applications to much larger systems.
These elastic models have also been utilized for large scale conformational transitions, and can yield information about intermediate forms. Recent applications have been made to the maturation of virus capsid structures and to the motions of the ribosome.
R. L. Jernigan1,*
1Laurence H. Baker Center for Bioinformatics and Biological Statistics