New York, NY (February 21, 2002) -- In biology, a special place is held by those who find simple physical ways to explain phenomena that are otherwise difficult to understand. That is the achievement of two scientists -- Dr. Diana Murray of the Department of Microbiology and Immunology at Weill Cornell Medical College and Dr. Barry Honig of the Department of Biochemistry and Molecular Biophysics at Columbia University -- who, in a cover article in the January issue of Molecular Cell, show that calculations of the electrostatic properties of protein domains known as C2 domains can explain their interactions with cellular membranes.

The paper's importance is evident in that it has been selected for attention and commentary in two other journals, Science and Developmental Cell. As Dr. Carl Nathan, Chairman of Weill Cornell's Department of Microbiology and Immunology, puts it, computational biology such as is exemplified by Drs. Murray and Honig's paper "is only now beginning to find a venue in the top-flight experiment-oriented journals."

In cell biology, proteins are often made up of several different domains -- "like beads on a string," says Dr. Murray, who is an assistant professor at Weill Cornell. The protein itself is often too big and complicated to be studied in intact form, but by examining
individual domains in isolation, scientists are able to obtain clues as to their role in cellular function.

The domains known as C2 domains are found in a wide variety of proteins. "The best-studied C2 domains are involved in signal transduction . . . and in membrane trafficking and fusion . . ." the authors write, "but there are many others whose functions have not yet been assigned . . . The C2 domains that have been characterized thus far serve principally as membrane-docking modules, a role that in many cases is controlled by calcium." "Membrane-docking" involves the binding of a protein to either the inner surface of the plasma membrane (a cell's outer boundary) or to intracellular membranes (which comprise the boundaries of the cell's internal organelles). Subcellular targeting mediated by C2 domains facilitates the flow of information within and among cells.

Drs. Murray and Honig performed computer simulations with several C2 domains whose structures had been experimentally determined, fitting these structures into the language of classical electrostatics using finite-difference Poisson-Boltzmann calculations. These calculations generalize Coulomb's Law (which describes the force of attraction or repulsion between electric charges) to any number and arrangement of charged groups, and they account for the complex effects of the shapes of biological macromolecules.

The calculations of the binding free energies of C2 domains to different types of membranes, in either the presence or absence of calcium (an important intracellular signal), explained the observed tendencies of different C2 domains to interact with either the negatively charged plasma membrane or more electrically neutral intracellular membranes.

The authors write, "Our calculations also account for the observed membrane- binding behavior of" mutant forms of certain C2 domains. "In addition," Dr. Murray says, "our computational methods provide experimentally testable predictions related to function." An example is the membrane-binding behavior of the C2 domain of the PTEN (pronounced "p-ten") tumor suppressor. This C2 domain is highly positively charged, and the calculations predict that it could anchor the intact protein constitutively at the plasma membrane surface. Thus, when a growth-inducing event leads to the production of an important signaling lipid called PI3P in the plasma membrane, membrane-associated PTEN is positioned to chew up the lipid, thus rapidly shutting down the signal and circumventing aberrant growth or tumor formation.

Dissecting these regulatory processes at the molecular level is important for understanding the formation of diseases like cancer and may one day facilitate the design of appropriate clinical treatments.