Location: JHE 326H
The primary objective in de novo protein design is to determine the amino acid sequences which are compatible with specific template backbone structures that may be rigid or flexible. It is of fundamental importance since it addresses the mapping of the space of amino acid sequences to known protein folds or postulated/putative protein folds. It is also of significant practical importance since it can lead to the improved design of inhibitors, design of novel sequences with better stability, design of catalytic sites of enzymes, and drug discovery.
The first part of this presentation will provide a motivation for the de novo protein design problem with flexible backbone template structures and an overview of the advances and limitations of the existing approaches. The second part will introduce a novel two stage approach which takes into account explicitly the flexibility of the templates. The first stage addresses the in silico sequence selection problem. The second stage addresses the fold specificity by performing structure prediction calculations using atomistic level force fields and the first principles approach, Astro-Fold. The probabilities of each sequence to fold specifically to the flexible templates are calculated. The third part will introduce an approach for the prediction of approximate binding affinities in protein-peptide complexes. Prediction results for several systems that include variants of Compstatin, human beta defensins, C3a, inhibitors for Complement C3c, and entry inhibitors for HIV-1 will be presented
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