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Sequence diversity and antibiotic resistance - a molecular model of short- and long-range effects of mutations in serine lactamases

Subject Area Biochemistry
Term from 2004 to 2007
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 5427265
 
How do enzymes achive subrate specifity? More specifically, how do structural elements and individual residues contribute to substrate recognition? Serine lactamases are an interesting model to study the effect of exchange of individual residues on specifity. Due to enhanced selective pressure imposed by application of antibiotics, natural evolution has resulted in a broad variety of serine lactamase variants with activity towards extended-spectrum cephalosporins. Some of the mutations are in the substrate binding site and directly interact with the substrate, but many changes occur far from the substrate. While there are suggestions to describe short-range effects of mutants, the mechanism of long-range effects is not yet understood. Long-range effects are frequently observed in mutants created by diected evolution approaches. The goal of this project is to etablish a general, generic molecular model of specifity which describes short- and long-range effects of mutations on structure and dynamics of the protein and realtes them to biochemical properties. It is based on large-scale molecular dynamics simulations of variants in complex with covalently bound substrate intermediates, solvated in a water box. This modelling approach will then be generalized to other enzyme classes. Because no constraints are applied, the model is also capable of investigating the effect of different solvents.
DFG Programme Priority Programmes
Participating Person Professor Dr. Rolf Schmid
 
 

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