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Computation and Theory of Cell Signaling and Molecular Transport
Research Interest
· Computer Simulation of Cell Signaling and Molecular Transport
· Structure based Drug Design
· Signaling Complexes
· Membrane-protein Interaction
· Structure and Dynamics of Interfaces
· Allostery in Supramolecular Assemblies
A major interest of our lab is to understand the thermodynamic principles of specificity in cell signaling and molecular transport by means of computational and theoretical techniques. The advent of petaflop computational resources and the fast-paced progress in coarse-grained modeling create unprecedented opportunities for simulating processes that span a vast range of time and length scales, such as cell signaling and molecular transport. These computational studies will allow us to investigate normal and aberrant properties of protein-protein and protein-membrane complexes in atomic detail. Other areas of interest include the basis of allosteric communication in signaling complexes, enzyme catalysis, molecular recognition and drug design. We develop and apply a variety of computational techniques, including classical and advanced molecular and Brownian dynamics simulations, structural bioinformatics, binding free energy calculations and related methods. Results from these studies will be the engines of new concepts and hypotheses to drive discovery efforts and experimental work.
Current projects include the spatiotemporal membrane organization of Ras proteins and their reaction partners, the driving forces for the membrane translocation of positively charged proteins and peptides, identification of novel allosteric sites in proteins and characterization of the communication between those sites. These projects are carried out in close collaboration with experimental labs.
A tutorial in my laboratory would provide experience with modern techniques in biomolecular simulations, including molecular dynamics and Brownian dynamics simulations; structure based drug design; structural boinformatics; continuum electrostatics and theoretical approaches for investigating the thermodynamic principles underlying the assembly and function of supramolecular complexes.
Recent Publications
Khavrutskii I, Gorfe AA, Lu B-Z and McCammon JA
Free energy for the permeation of Na+ and Cl- ions and their ion-pair through zwitterionic dimyristoyl phosphatidylcholine lipid bilayer by umbrella integration with harmonic fourier Beads.J. Am. Chem. Soc. 2009, 131:1706-16.
Grant B, Gorfe AA and McCammon J.A., Ras Conformational Switching: Simulating Nucleotide Dependent Conformational Transitions with Accelerated Molecular dynamics. PLoS Comput. Biol.,
2009, 5: e1000325.
Gorfe, A. A.; McCammon, J. A., Similar Membrane Affinity of Mono- and Di-S-acylated Ras Membran Anchors: A New Twist in the Role of Protein Lipidation.
J. Am. Chem. Soc. 2008, 130, 12624-12625.
Gorfe, A. A.; Baron, R.; McCammon, J. A., Water-membrane partition thermodynamics of an amphiphilic lipopeptide: An enthalpy driven hydrophobic effect.
Biophys J. 2008, 95, 3269-3277.
Gorfe, A. A.; Grant, B. J.; McCammon, J. A., Mapping the nucleotide and isoform dependent structural and dynamical features of Ras proteins.
Structure 2008, 16, 885-896.
Abankwa, D.; Hanzal-Bayer, M.; Ariotti, N.; Plowman, S. J.; Gorfe, A. A.; Parton, R. G.; McCammon, J. A.; Hancock, J. F., A novel switch region regulates H-ras membrane orientation and signal output.
EMBO J 2008, 27, 727-735.
Gorfe, A. A.; Babakhani, A.; McCammon, J. A., Free Energy Profile of H-ras Membrane Anchor upon Membrane Insertion.
Angew Chem Int Ed Engl 2007, 46, 8234-8237.
Gorfe, A. A.; Babakhani, A.; McCammon, J. A., H-ras protein in a bilayer: interaction and structure perturbation.
J Am Chem Soc 2007, 129, 12280-12286.
Gorfe, A. A.; Hanzal-Bayer, M.; Abankwa, D.; Hancock, J. F.; McCammon, J. A., Structure and dynamics of the full-length lipid-modified H-Ras protein in a 1,2-dimyristoylglycero-3-phosphocholine bilayer.
J Med Chem 2007, 50, 674-684.
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