Paper Citing NAMD - Abstract
Janosi, Lorant; Gorfe, Alemayehu A.
Segregation of Negatively Charged Phospholipids by the Polycationic and Farnesylated Membrane Anchor of Kras
BIOPHYSICAL JOURNAL, 99:3666-3674, DEC 1 2010
The Kras protein a member of the Ras family of bio switches that are frequently mutated in cancer and develop mental disorders becomes functional when anchored to the inner surface of the plasma membrane It is well known that membrane attachment involves the farnesylated and poylcationic C terminus of the protein However little is known about the structure of the complex and the specific protein lipid interactions that are responsible for the binding On the basis of data from extensive (>0 55 mu s) molecular dynamics simulations of multiple Kras anchors in bilayers of POPC/POPG lipids (4 1 ratio) we show that as expected Kras is tethered to the bilayer surface by specific lysine POPG salt bridges and by nonspecific farnesyl phospholipid van der Waals interactions Unexpectedly however only the C terminal five of the eight Kras Lys side chains were found to directly interact with the bilayer with the N terminal ones staying in water Furthermore the positively charged Kras anchors pull the negatively charged POPG lipids together leading to the clustering of the POPG lipids around the proteins This selective Kras POPG interaction is directly related to the specific geometry of the backbone which exists in two major conformational states 1) a stable native like ensemble of structures characterized by an extended geometry with a pseudohelical turn and 2) less stable nonnative ensembles of conformers characterized by severely bent geometries Finally although the interface bound anchor has little effect on the overall structure of the bilayer it induces local thinning within a persistence length of similar to 12 A Our results thus go beyond documenting how Kras attaches to a mixed bilayer of charged and neutral lipids they highlight a fascinating process of protein induced lipid sorting coupled with the (re)shaping of a surface bound protein by the host lipids
