College of Liberal Arts & Sciences

Identification and characterization of non-covalent interactions that drive binding and specificity in DD-peptidases and β-lactamases

Tuesday, April 15, 2014

April 15, Wed 2014
1:00 pm, MRB 200

Dr. H. Lee Woodcock

Department of Chemistry, University of South Florida

Identification and characterization of non-covalent interactions that drive binding and specificity in DD-peptidases and β-lactamases

Bacterial resistance to standard (i.e. β-lactam-based) antibiotics has become a global pandemic. One possible key to unraveling critical details is characterization of the non-covalent interactions that govern binding and specificity (DD-peptidases, antibiotic targets, versus β-lactamases, the evolutionarily derived enzymes that play a major role in resistance) and ultimately resistance as a whole. Results of a detailed computational analysis targeted at elucidating these effects will be presented. Specifically, an extended π-π network is elucidated that suggests antibacterial resistance has evolved, in part, due to stabilizing aromatic interactions. Additionally, interactions between the protein and peptidomimetic substrate are identified and characterized; revealing an interaction that may significantly contribute to β-lactam speci- ficity. Finally, interaction information is used to suggest modifications to current β-lactam compounds that should both improve binding and specificity in DD-peptidases and their physiochemical properties.

Further complicating the development of new anti-biotics is the lack of knowledge about key active site protonation states for bacterial peptidases (e.g., Streptomyces R61 DD-peptidase). The protonation state and function for two active site residues (Lys65 and His298) was examined in a R61-benzylpenicillin non- covalent complex. It was concluded that Lys65 is likely to be in its natural base form, while His298 is protonated and primarily serves as a stabilizing residue for the protein-ligand complex. He hypothesize that Lys65 is involved in the acylation reaction, so the identity of its protonation state upon ligand binding serves as an important precursor to the elucidation of the mechanism. Our novel computational approach was validated by examining a related β-lactamase system and comparing to a high-resolution crystal structure.



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