In this presentation, we will discuss the design of protein-protein inhibitors that derive their affinity, in part, from quantum resonance (polarizability and charge sharing of ligand and protein). A well-known example of quantum resonance is biotin-avidin/streptavidin complex�femtomolar, reversible binding�and is considered an outlier because it exceeds calculations of affinity from free energy scoring functions and binding studies. If biotin-like interactions could be predicted and replicated, the existing experience that these interactions are outliers would be changed. We applied a Monte Carlo fragment-based approach to probe the surface of proprotein convertase subtilisin/kexin type 9 (PCSK9)�a  target for the treatment of hypercholesterolemia and coronary heart disease�and found a novel site on PCSK9 at the low-density lipoprotein receptor recognition domain that is considered a hot spot, site of high interaction energy. The same approach was applied to RecA�a protein essential for up-regulating the translation of bacterial proteins responsible for DNA mutations that result in antibiotic resistance�and found three hot spots, one at the ATP binding site, one at the single-stranded DNA binding site, and one in the polymerization interface. Using quantum mechanical evaluation with fragment-based simulations, we found that certain polarizable fragments bound to the hot spots and can achieve the charge sharing at a level near that of biotin-streptavidin.  We believe that this quantum resonance�polarizability and charge sharing of ligand and protein�is a contributor to extreme high affinity ligands. Being able to predict these interactions in a fast and efficient way could have transformative outcomes for understanding biomolecular recognition and for ligand design thus impacting a broad class of discovery programs.

Contribution to affinity from quantum resonance: A fragment-based approach to RecA and PCSK9

244th National Meeting (2012)

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