The Laboratory of Physical and Structural Biology is staffed largely by physicists who take an integrative approach to the disciplines of physics, biology, and chemistry. They see the next step in structural biology not simply as determining the structures of every identifiable entity from molecule to organelle but rather as learning how these structures work through the physics and chemistry of the intermolecular forces that drive them. Only then can we learn from the increasing number of protein, nucleic acid, saccharide, and lipid structures how to design agents that compete effectively with deviant interactions associated with disease. It is gratifying to see that the physics they have developed, which explains bio-matter, is finding applications outside biology.

By reconstituting an OmpF into lipid bilayers and monitoring interference with channel conductance, members of the laboratory, led by Sergey Bezrukov, have been able, during the past year, to mimic the passage of an antibiotic such as ampicillin through a bacterial trans-membrane ionic channel. One remarkable lesson from this observation is that weak binding of ampicillin, as revealed by extended residence times, improves the antibiotic’s chances of making it all the way through to the other side.

Don Rau’s group has been able to show how solution conditions modify the specific versus non-specific binding of proteins to DNA. Thus, under osmotic stress, DNA/protein association involves about 100 more intervening water molecules in non-specific than in specific association; the difference is seen in association constants as well as in rates of dissociation.

Adrian Parsegian’s group has formulated the strength and range of forces that stabilize membranes used in drug-delivery systems. Created by polymers bound to lipid bilayer membranes, these forces have been previously measured and are now correlated with the osmotic pressures of the same polymers in solution. Using the correlation, the group can now design polymer-stabilized systems more systematically than was formerly possible.