Abstract
β-lactam antibiotics target DD-transpeptidases, enzymes that perform the last step of bacterial cell-wall synthesis. To block the antimicrobial activity of these antibiotics, bacteria have evolved lactamases that render them inert. Among these, TEM-1, a class A lactamase, has been extensively studied. In 2004, Horn et al. described a novel allosteric TEM-1 inhibitor, FTA, that binds distant from the TEM-1 orthosteric (penicillin-binding) pocket. TEM-1 has subsequently become a model for the study of allostery. In the present work, we perform molecular dynamics simulations of FTA-bound and FTA-absent TEM-1, totaling ~3 μS, that provide new insight into TEM-1 inhibition. In one of the simulations, bound FTA assumed a conformation different than that observed crystallographically. We provide evidence that the alternate pose is physiologically plausible and describe how it impacts our understanding of TEM-1 allostery.