V. Adrian Parsegian, PhD, Chief

The research conducted by the Laboratory of Physical and Structural Biology (LPSB) is motivated by the need to bring together many types of science. The next step in structural biology is not simply to determine the structure of every identifiable entity from molecule to organelle. Rather, it is to learn how the structures work through the physics and chemistry of the intermolecular forces that create them. Then, it will be possible to 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.

Polymer partitioning into the highly confined spaces of protein voids under the crowded circumstances of cellular life is a long-standing challenge for physicists working in biology. One of the theoretical studies undertaken this year in the Section on Molecular Transport, led by Sergey Bezrukov, rationalizes recently measured partitioning of polyethylene glycol from bathing solutions of varying polymer concentration into alpha-hemolysin channels. To explain the concentration dependence of the partition coefficient, the theory recognizes that non-ideality of polymer solution in the pore is weak because the overlap volume fraction of the polymer in the pore is higher than that in the bulk. The reason is that polymer molecules in the pore form cigar-shaped structures with high intramolecular monomer density.

Donald Rau's Section on Macromolecular Recognition and Assembly directly measures forces between biological macromolecules in macroscopic condensed arrays, using osmotic stress and x-ray scattering. The universality of the force characteristics observed for a wide variety of macromolecules, including DNA, proteins, lipid bilayers, and carbohydrates, reveals that the energy associated with changes in structuring water between close surfaces dominates intermolecular forces. To investigate the role of water in the interaction of individual molecules, the Section measures and correlates changes in binding energies and hydration accompanying specific recognition reactions of biologically important macromolecules, particularly of sequence-specific DNA-protein complexes.

Building on lessons learned while writing a text on van der Waals forces, Adrian Parsegian and collaborators in the Section on Molecular Biophysics are now examining these forces in evidence in a wide variety of biomaterials. In keeping with the theme of relating molecular forces to cellular organization, the Section has been able to predict and observe new ways in which salts and small molecules change the assembly of lipid membranes and to design experiments that show how macromolecular organization responds to deliberate changes in solution properties.