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Assistant Professor of Biochemistry and Biophysics
Ph.D. Johns Hopkins University Medical School 2000

Investigating membranes and membrane proteins via computer simulation

My research interests revolve around the use of computer modeling to understand the structure and thermodynamics of biological molecules. In particular, I am most interested understanding the biology and physics of peptide-membrane and peptide-protein interactions. These interactions underly a fantastic array of biological processes, from cell division and membrane fusion (fusion proteins) to antimicrobial action (cytotoxic peptides), to cell signaling (through membrane composition-dependent modulation of protein function, as seen for rhodopsin), to immune response (MHCs) and even nutrition (peptide binding proteins).

In my peptide-membrane research, I will focus on two questions: How do cytotoxic peptides attack cell membranes? How do variations in membrane lipid composition affect this mechanism? Answering these questions will clarify the mechanisms evolution has devised for species-specific cellular defense. My planned approach combines existing molecular simulation techniques with the development of new implicit models for protein-lipid interactions. I have begun by focusing on a new class of antimicrobial peptides known as lipopeptides. By analyzing molecular dynamics simulations of two different peptides (one selective for bacteria, the other not selective) bound to membrane compositions chosen to resemble bacterial and mammalian membranes, I hope to understand the molecular mechanism underlying species-selectivity.

My primary model for examining peptide-protein interactions is the Oligopeptide binding protein (OppA) from gram-negative bacteria. The existence of crystallographic and calorimetric data for this protein binding roughly 30 separate ligands makes it an ideal test bed to interrogate the energetics of association: How does the protein stabilize the peptide backbone? What is the role of water in the protein binding cavity? I plan to attack these questions using a broad range of simulation techniques, from all-atom molecular dynamics and advanced sampling methods to more approximate multi-scale approaches. The insights I develop using these calculations will allow me to examine other roles of peptide binding, such as cellular recognition and immune response.

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Recent Publications

Lau PW, Grossfield A, Feller SE, Pitman MC, Brown MF (2007) Dynamic structure of retinylidene ligand of rhodopsin probed by molecular simulations. J Mol Biol, 372:906-17

O'Neil L L, Grossfield A, Wiest O (2007) Base Flipping of the Thymine Dimer in Duplex DNA. J Phys Chem B,

Grossfield A, Feller SE, Pitman MC (2007) Convergence of molecular dynamics simulations of membrane proteins. Proteins, 67:31-40

Jiao D, King C, Grossfield A, Darden TA, Ren P (2006) Simulation of Ca2+ and Mg2+ solvation using polarizable atomic multipole potential. J Phys Chem B, 110:18553-9

Grossfield A, Feller SE, Pitman MC (2006) Contribution of omega-3 fatty acids to the thermodynamics of membrane protein solvation. J Phys Chem B, 110:8907-9

Grossfield A, Feller SE, Pitman MC (2006) A role for direct interactions in the modulation of rhodopsin by omega-3 polyunsaturated lipids. Proc Natl Acad Sci U S A, 103:4888-93

Martinez-Mayorga K, Pitman MC, Grossfield A, Feller SE, Brown MF (2006) Retinal counterion switch mechanism in vision evaluated by molecular simulations. J Am Chem Soc, 128:16502-3

Grossfield A (2005) Dependence of ion hydration on the sign of the ion's charge. J Chem Phys, 122:024506

Pitman MC, Grossfield A, Suits F, Feller SE (2005) Role of cholesterol and polyunsaturated chains in lipid-protein interactions: molecular dynamics simulation of rhodopsin in a realistic membrane environment. J Am Chem Soc, 127:4576-7

Drozdov AN, Grossfield A, Pappu RV (2004) Role of solvent in determining conformational preferences of alanine dipeptide in water. J Am Chem Soc, 126:2574-81

Grossfield A, Ren P, Ponder JW (2003) Ion solvation thermodynamics from simulation with a polarizable force field. J Am Chem Soc, 125:15671-82

Petrache HI, Grossfield A, MacKenzie KR, Engelman DM, Woolf TB (2000) Modulation of glycophorin A transmembrane helix interactions by lipid bilayers: molecular dynamics calculations. J Mol Biol, 302:727-46

Grossfield A, Sachs J, Woolf TB (2000) Dipole lattice membrane model for protein calculations. Proteins, 41:211-23

Woolf TB, Grossfield A, Tychko M (2000) Differences between apo and three holo forms of the intestinal fatty acid binding protein seen by molecular dynamics computer calculations. Biophys J, 78:608-25

Graduate students in my laboratory work toward a Ph.D. degree in the following program[s]:

Ph.D. in Biochemistry
Ph.D. in Biophysics

Ph.D. candidates in my laboratory may also be affiliated with these programs:

Contact Information

E-Mail: alan_grossfield@urmc.rochester.edu

Alan Grossfield
Department of Biochemistry and Biophysics
University of Rochester School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester, New York 14642

Office: Medical Center 3-6812
Telephone: (585) 276-4193; Fax: (585) 275-6007