Project abstract for group kaznessi

Multiscale Models of Antibiotic Cellbots

A significant need exists to develop technologies to control colonization and transmission of enterococci, as these microorganisms are becoming an escalating threat to mankind. Over the last three decades enterococcal strains have evolved to resist almost all antibiotics, including vancomycin, long considered an antibiotic of last resort for many infections. Patients with VRE infection have increased mortality, morbidity, length of hospital stay, and hospital costs, in comparison to uninfected groups. These researchers are studying bacteriocins that target VRE. Bacteriocins are defined as ribosomally synthesized peptides produced by bacteria that inhibit the growth of other closely related bacteria. The researchers will focus on class IIa and classIIb enterocins. For both classes of bacteriocins, peptide-membrane interactions are responsible for function. With molecular simulations the group will explain experimental observations of activity and determine the sequence and structural features of these peptides that underlie function. They have developed models that quantify the molecular interactions between antimicrobial peptides and cell membranes, the loss of membrane structural integrity, the collapse of the transmembrane potential, cell lysis and death. With these models, a clear timeline of biophysical steps that underlie AMP function can be generated. Consequently, peptide sequence and structure may be correlated to antimicrobial activity. The researchers use NAMD with the CHARMM forcefield. The details of the simulation protocol vary slightly in each case, but the following key features are common to all: a two-femtosecond time step for all calculations, along with SHAKE restraints on all bonds involving hydrogen; the CHARMM c36 force field along with the TIP3P water model; the use of particle mesh Ewald (PME) summation for the treatment of long-range electrostatic forces; and a potential cutoff of 10Å, smoothly decreased to zero between 9 and 10 Å. 

A bibliography of this group’s publications acknowledging MSI is attached.