Electric fields determine carbapenemase activity in class A β-lactamases

Abstract

Antimicrobial resistance is a public health crisis. Limited understanding of the catalytic drivers in resistance-mediating enzymes such as {beta}-lactamases hinders our ability to combat this crisis. Here, we dissect the catalytic contributions of active-site electric fields in class A {beta}-lactamases. We studied the enzymatic hydrolysis of a carbapenem antibiotic by QM/MM molecular dynamics simulations and quantified active-site fields with a custom-made script. We discovered that the fields correlate well with activity and identified seven positions, some distal, that distinguish efficient carbapenemases. Electric-field analysis may help predict the activity of {beta}-lactamases and guide antibiotic and enzyme design. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/565607v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@15ee41aorg.highwire.dtl.DTLVardef@d1a11corg.highwire.dtl.DTLVardef@a83bd7org.highwire.dtl.DTLVardef@f0abdf_HPS_FORMAT_FIGEXP M_FIG C_FIG Electric field script: www.github.com/bunzela/FieldTools