Professor Carlos Simmerling
Laufer Center for Physical and Quantitative Biology
Stoney Brook University
Stone Brook, NY

Monday, March 11, 2019
3:00 pm (CT)
3269 Beckman Institute

Abstract

In contrast to proteins recognizing small-molecule ligands, DNA-dependent enzymes cannot rely solely on interactions in the substrate-binding site to achieve their exquisite specificity. It is widely believed that substrate recognition by such enzymes involves a series of conformational changes in the enzyme-DNA complex with sequential gates favoring cognate DNA and rejecting nonsubstrates. However, direct evidence for such mechanism is limited. We used state of the art molecular dynamics methods to explore the dynamic recognition of oxidative DNA damage by glycosylase enzymes. The resulting free energy landscapes, supported by biochemical analysis of site-directed mutants disturbing the interactions along the proposed path, show that the glycosylases selectively facilitate recognition dynamics, helping the rapidly sliding enzyme avoid full extrusion of every encountered base for interrogation. Lesion recognition through gating intermediates may be a common theme in DNA repair enzymes; we show that human and bacterial enzymes share a common recognition mechanism despite lack of sequence or structural similarity of their glycosylases.