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Colloquium - Ivanov

The Interplay of AAA+ Molecular Machines and Sliding Clamps at the DNA Replication Fork
University of California, San Diego
2/24/2009
4:00pm-5:00pm

Replication of chromosomal DNA is accomplished by a dynamic protein assembly termed the replisome. Within the replisome, the function of replicative DNA polymerases is to rapidly and faithfully duplicate the cell's genetic material prior to cell division. During replication proliferating cell nuclear antigen (PCNA, sliding clamp) serves as an accessory protein whose role is to topologically tether DNA polymerase to DNA. PCNA also acts as a scaffold in the recruitment of proteins involved in cell-cycle control and DNA repair. Mounting recent experimental evidence has pointed to the involvement of sliding clamps in almost every aspect of DNA metabolism. Yet many mechanistic details of how these fascinating proteins are loaded onto DNA and function within the machinery of the replisome have remained unknown.

To perform its vital functions the clamp has to be opened and resealed at DNA primer-template junctions by the action of a clamp loader ATPase -- replication factor C (RFC). Recent computational work on the RFC/PCNA complex will be presented. It established that upon clamp opening the complex undergoes a large conformational rearrangement, leading to the formation of an extended interface between the surface of the sliding clamp and RFC. An interface complementary to ring-open PCNA transforms the free energy landscape underlying the closed- to open state transition, effectively trapping PCNA in an open conformation. Thus, careful comparison of free energy profiles for clamp opening in the presence and absence of RFC has allowed us to substantiate the role of the clamp loader in the initial stage of the clamp-loading cycle.

Dr. Ivaylo Ivanov is a postdoctoral fellow with J. Andrew McCammon and John Tainer in the Chemistry and Molecular Biology departments at the University of California, San Diego. Dr. Ivanov's postdoctoral work uses ab initio and classical molecular dynamics, combined with quantum mechanics/molecular mechanics (QM/MM) computations. His objectives are to examine enzymatic reactions catalyzed by DNA repair enzymes (endonuclease IV, APE1), by modeling dynamic fluctuations and conformational reorganization within realistic models of protein-nucleic acid assemblies. He is also using MM to simulate interactions of the DNA sliding clamp, proliferating cell nuclear antigen (PCNA), with DNA and repair enzymes. Finally, Dr. Ivanov is exploring global conformational dynamics and energetics of ion permeation in Cys-loop receptors involved in synaptic neurotransmission.

Dr. Ivanov obtained a PhD in Chemistry in 2004, working with Michael Klein at the University of Pennsylvania. There, he performed computationally demanding first principles simulations of catalysis by arginase, a multinuclear metalloenzyme. He also studied the utility of the Car-Parrinello method in determining free energies in aqueous systems and pKa, and investigated proton transfer mechanisms with Car-Parrinello molecular dynamics. Finally, he implemented a variant of the fast multipole method in the form of a C++ class library.

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