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Implications of the Small Number of Distinct Ligand Binding Pockets in Proteins for Drug Discovery, Evolution and Biochemical Function

By Jeff Skolnick
Center for the Study of Systems Biology, Georgia Institute of Technology

The intrinsic ability of protein structures to exhibit the geometric and sequence properties required for ligand binding without evolutionary selection is shown by the coincidence of the properties of pockets in native, single domain proteins with those in computationally generated, compact homopolypeptide, artificial structures, ART. The library of native pockets is covered by a remarkably small number of representative pockets (~400), with virtually every native pocket having a statistically significant match in the ART library, suggesting that the library is complete. When sequences are selected for ART structures based on fold stability, pocket sequence conservation is coincident to native. The fact that structurally and sequentially similar pockets occur across fold classes combined with the small number of representative pockets in native proteins implies that promiscuous interactions are inherent to proteins. Based on comparison of PDB and ART structures and pockets, the widespread assumption that the co-occurrence of global structure, pocket similarity, and amino acid conservation demands an evolutionary relationship between proteins is shown to significantly underestimate the random background probability. Indeed, many features of biochemical function arise from the physical properties of proteins which evolution likely fine-tunes to achieve specificity. This study suggests that a repertoire of thermodynamically (marginally) stable proteins could engage in many of the biochemical reactions needed for living systems without selection for function, a conclusion with significant implications for the origin of life.  Finally, examples of experimental validation of small molecule hits that exploit the degeneracy of ligand binding pockets are presented. Most promising is the prediction and clinical validation of the repurposing of an FDA approved drug to treat chronic fatigue syndrome.