Rational drug design relies on accurately and efficiently estimating the binding energies of drug candidates to a protein. There is now experimental evidence that the protonation states (and, hence, the charges) of functional groups in both the protein and ligand can change upon binding, and significantly alter the binding energy. However, this phenomenon is not included in any rational drug design studies.
My goals are to:
(1) extend our current protein pKa prediction methodology (PROPKA) to include the effect of ligand binding on pKa predictions and undertake systematic studies of hundreds of protein-ligand structures to determine
(2) how often it occurs and
(3) how much, on average, it contributes to the binding energy.
The PROPKA method is an empirical pKa predictor developed by the Jensen group, and is among the fastest, most accurate, and easiest to use protein pKa prediction methodology currently available. An on-line version is available (since January 2005) and has been accessed more than 24,000 times. My ultimate goal is to include part of my PROPKA program in docking programs used for rational drug design
Call for proposal
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