Collaborative Research: Ordering Processes in Water Aqueous Solutions and Water-Biomolecule Systems

Intellectual Merit Cooperative processes involve the sudden and concerted participation of a large number of basic units: amino acid residues in protein folding, proteins in fibrilization, small molecules in first-order phase transitions, complex molecules in self-assembly. The result of such concerted action is all-or-nothing observable behavior over microscopic (protein folding), mesoscopic (fibrilization), or macroscopic (phase transitions) length scales. The control of these processes by manipulation of solvent composition or thermodynamic conditions has been the unifying theme underlying our collaboration under the previous funded period, and remains so in this renewal application. Building upon our scientific accomplishments over the past five years, we propose to investigate collaboratively a wide range of fundamental problems involving all-or-nothing behavior and its tuning: Experiments on glass-phase protein folding in which this process takes place over macroscopic times of our choice (minutes); Computer simulations of temperature-, pressure-, and solvent composition effects on protein fold stability; Computer simulations of phase transitions in two-scale spherically-symmetric model systems that exhibit water-like dynamics and solvation thermodynamics; Theoretical and computational investigations of protein phase diagrams and directed evolution using water-explicit lattice models; Experiments on protein fibril formation and its reversal in protic ionic liquids, and complementary simulations; Computational studies of the emergence of molecular mobility upon hydration of protein powders. In each case, we seek to understand the structure, dynamics or thermodynamics of the entity undergoing a cooperative transition, and the use of solvent composition, temperature, or pressure to tune the emergence of all-or-nothing behavior. Our collaboration during the past five years has been more than the sum of its parts. The diversity of backgrounds and perspectives contributed by an experimental physical chemist (Angell), a chemical engineer (Debenedetti), a theoretical chemist (Rossky), and two computational physicists (Stanley and our non-US collaborator Sastry) has produced findings that transcend the expertise of any one of us. Out of the many examples described in the proposal, we highlight two: the first laboratory vitrification of a monatomic metallic liquid, made possible by theoretical and computational work on liquid-liquid and glass transitions in water-like model atomic systems with directional interactions (Arizona-Bangalore collaboration); the computational discovery of protein-like cold unfolding of a hydrophobic polymer in a model solvent with two characteristic length scales, made possible by computational work on two-scalesystem thermodynamics, and theoretical work on the statistical mechanics and thermodynamics of hydrophobic hydration (Boston-Texas-Princeton collaboration). This renewal proposal is predicated on the continuation and improvement of this collaboration. Broader Impact The topics addressed in this proposal have implications that go far beyond their inherent scientific interest. These include the long-term storage and preservation of therapeutic drugs, the molecular mechanisms of neurodegenerative diseases and type II diabetes, the design of advanced materials by selfassembly, and the development of new proteins with improved stability characteristics in non-aqueous environments, or at extreme temperatures and pressures. As has been the case during the past five years, we will continue to train graduate students and post-docs in theoretical chemistry, state-of-the-art computer simulations, and experimental techniques including calorimetry, electron microscopy, infrared and ultraviolet spectroscopy. Student exchanges between participating laboratories (including our overseas collaborator Srikanth Sastry at the Nehru Institute for A