TCB Seminar

New Developments in the CHARMM Lipid Force Field and Applications to Membrane-associated Proteins

Professor Jeffery Klauda
A. James Clark School of Engineering
University of Maryland
College Park, MD

Monday, May 7, 2018
3:00 pm
3269 Beckman Institute


The pairwise additive force field in CHARMM (CHARMM36, C36) is the most diverse and accurate all-atom force field for lipids. Development of common lipids required an extensive effort and progress continues with more exotic lipids. This lecture will present work on developing an ether lipid force field important to membranes of archaea and those of mammalian neurons. Moreover, the future of the lipid force field will be discussed and what is needed to make the pairwise additive force field better and not depend on cutoffs using the Lennard-Jones Particle Mesh Ewald (LJ- PME) method (Leonard et al. J. Chem. Theory Comput. 14: p948). In a the second part of this talk, the C36 lipid force field will be used in applications to study a transmembrane protein (α-hemolysin, α-HL) and a section of a peripheral membrane protein that senses lipid curvature or packing. The amphipathic lipid packing sensor (ALPS) motif of the oxysterol binding protein homologue (Osh4) was studied with μs all-atom molecular dynamics (MD) simulations. The Highly Mobile Membrane-Mimetic Model (BJ, 102: p2130) was then used to verify that the mechanism and bound structure conforms to that of the expensive μs all- atom lipid MD simulations. Our results suggest that the HMMM model not only preserves equilibrium structure of peptide binding but also the mechanism of peptide binding ,while enhancing binding timescales by an order of magnitude with the proper lipid packing density. Our simulations of α-HL probe the importance of membrane equilibration and lipid type to protein structure and function. This protein has the potential to sequence DNA and measure various biopolymer analytes. Our MD simulations demonstrate that the ion current through the protein channel depends strongly on the lipid membrane and hydrophobic mismatch. This protein/membrane mismatch can lead to deformation of the proteinís channel and reduction of current. Therefore, careful interpretation of experimentally-measured current in the presence of DNA in the pore depends also on the lipid environment, which was not fully understood before.