Alan M. Grossfield, Ph.D.

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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.

Current Appointments

• Assistant Professor - Department of Biochemistry and Biophysics (SMD)

Lab Website

http://membrane.urmc.rochester.edu/Grossfield_Lab/Welcome.html

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Recent Journal Articles
Showing the 5 most recent journal articles. (16 available)
Khelashvili, G.; Grossfield, A.; Feller, S. E.; Pitman, M. C.; Weinstein, H.;. "Structural and dynamic effects of cholesterol at preferred sites of interaction with rhodopsin identified from microsecond length molecular dynamics simulations". Proteins 76 (2009): 403-17.
Grossfield, A.; Pitman, M. C.; Feller, S. E.; Soubias, O.; Gawrisch, K.;. "Internal hydration increases during activation of the G-protein-coupled receptor rhodopsin". J Mol Biol 381 (2008): 478-86.
Grossfield, A.; Feller, S. E.; Pitman, M. C.;. "Convergence of molecular dynamics simulations of membrane proteins". Proteins 67 (2007): 31-40.
O'Neil L, L.; Grossfield, A.; Wiest, O.;. "Base Flipping of the Thymine Dimer in Duplex DNA". J Phys Chem B (2007).
Lau, P. W.; Grossfield, A.; Feller, S. E.; Pitman, M. C.; Brown, M. F.;. "Dynamic structure of retinylidene ligand of rhodopsin probed by molecular simulations". J Mol Biol 372 (2007): 906-17.