The long-term goal of this work is to understand the molecular origins of the phase behavior of reversibly polymerizing systems. This phase behavior forms the basis for such normal processes as the assembly of cytoskeletal elements and cell membranes, and such pathological processes as the polymerization of hemoglobin in sickle cell disease, and the deposition of lipids in atherosclerosis. Studies of these systems have tended to ignore interactions between aggregates. However, these have an important influence on in vivo and in vitro behavior. In the work proposed here we will consider the effects of steric and electrostatic repulsions between aggregates on the size and orientation distributions of the aggregates and on the occurence of phase separation. By taking accunt of the solvent contained in protein polymers, and the possibilities for copolymerization and/or coalignment in mixtures of polymerizing proteins, we will be able to investigate a wider range of the phase behavior of polymerizing proteins than previously possible. By including the possibility of bidirectional growth of micelles, we will be able, for the first time, to explore the biaxial and lamellar phases of surfactants. The theoretical calculations will make use of variations of a lattice model to describe inter-particle interactions and a phenomenological model to describe intra-aggregate interactions. Reference will be made to complimentary experimental work: the theoretical results will inform the design and interpretation of experiments and the experimental data will serve to test theoretical predictions. By elucidating the molecular determinants of the highly cooperative phase behavior of reversibly polymerizing systems, we hope to be able to identify important points of normal and pathological control, and contribute to an improved conceptual framework for therapeutic strategies.
NIH ExPorter
NIH ExPorter