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The Department of Biomedicine

BBB Seminar: Ross C. Walker

Identifying novel drug targets with advanced molecular dynamics simulations: Application to adenovirus proteases 

Ross C. Walker
San Diego Supercomputer Center & Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA

A detailed understanding of the activation and reaction pathways of enzymes is critical to the development of next generation pharmaceuticals. The development of pathway and enhanced sampling methods, such as the nudged elastic band (NEB) algorithm and accelerated molecular dynamics (aMD) offers a way to use molecular dynamics simulations to study the activation and reaction pathways of enzymes at atomistic detail. This talk will introduce the concept of pathway and enhanced sampling methods, coupled with the use of graphics processor units (GPUs) to enable routine multiple microsecond long simulations, and show how such simulations can be used to find low energy activation and reaction pathways in enzymes. Application of these techniques will be illustrated using the specific example of the activation of the adenovirus protease (AVP).

The AVP is essential for adenovirus replication and thus is a target for antiviral drugs. The enzyme is activated upon the binding of a small peptide via a 53 amino acid signal transduction pathway. Recently obtained crystal structures of both the inactive and active forms of AVP provide the two end points of this pathway. This talk will highlight how pathway sampling techniques employing molecular dynamics have been used to characterize this pathway and identify potential drug targets.

Host: Knut Teigen , Department of Biomedicine