pMD-Membrane: A Method for Ligand Binding Site Identification in Membrane-Bound Proteins.
Probe-based or mixed solvent molecular dynamics simulation is a useful approach for the identification and characterization of druggable sites in drug targets. However, thus far the method has been applied only to soluble proteins. A major reason for this is the potential effect of the probe molecules on membrane structure. We have developed a technique to overcome this limitation that entails modification of force field parameters to reduce a few pairwise non-bonded interactions between selected atoms of the probe molecules and bilayer lipids. We used the resulting technique, termed pMD-membrane, to identify allosteric ligand binding sites on the G12D and G13D oncogenic mutants of the K-Ras protein bound to a negatively charged lipid bilayer. In addition, we show that differences in probe occupancy can be used to quantify changes in the accessibility of druggable sites due to conformational changes induced by membrane binding or mutation.
University of Texas Health Science Center at Houston, Department of Integrative Biology and Pharmacology, Houston, Texas, United States of America.
Priyanka
P
Prakash
University of Texas Health Science Center at Houston, Department of Integrative Biology and Pharmacology, Houston, Texas, United States of America.
Abdallah
A
Sayyed-Ahmad
University of Texas Health Science Center at Houston, Department of Integrative Biology and Pharmacology, Houston, Texas, United States of America.
Alemayehu A
AA
Gorfe
D000465:Algorithms; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry* / Q000648:ultrastructure*; D008051:Lipid Bilayers / Q000737:chemistry*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods; D012984:Software; D018631:ras Proteins / Q000737:chemistry* / Q000648:ultrastructure*
D008051:Lipid Bilayers; D018631:ras Proteins