CAREER: An Integrated Multiscale Platform for Fundamental Studies of Peptide Self-Assembly

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0845074Shell"This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)."An Integrated Multiscale Platform for Fundamental Studies of Peptide Self Assembly Peptides are exceptionally versatile platforms for tunable molecular self assembly, forming an impressive variety of nanoscale morphologies in response to cues spanning temperature, pH, salt, solvent, and chemical additives. Moreover, their high degrees of biocompatibility, conformational specificity, and molecular recognition have made these systems ideal candidates for bottom up design in materials, nanotechnology, medicine, and biotechnology. Yet despite successes in experimental peptide engineering, a predictive theoretical understanding that could be used to rationally design peptide self assembled materials is lacking. Specifically, there are no general, quantitative methods for understanding the impact of single residue mutations on assembly thermodynamics and kinetics, or for predicting the rich, diverse phase morphologies that different peptides can adopt.Intellectual Merit:The CAREER project involves the development of new multiscale simulation methods to overcome existing barriers to multipeptide modeling, and the use of these to generate new insights into the thermodynamics of peptide self assembly. This work develops a novel, general multiscale methodology that rigorously derives coarse grained peptide models from carefully performed all-atom simulations. At the heart of this approach is the relative entropy, a quantitative metric for linking models at different scales: optimized sequence specific coarse grained models will be developed by minimizing the relative entropy between coarse grained and reference all atom peptide dimer simulations. The reduced models developed will enable long time scale studies of large oligomeric assemblies that will provide new fundamental molecular perspectives on peptide self-assembly thermodynamics. Specifically, this work will study conformational switching peptides, a class of engineered peptides that react sensitively to environmental cues to transform among different self assembled nanostructures. The diversity of these peptides stands to delineate fundamental and sequence specific aspects of peptide self assembly, and provides a sensitive test of predictive simulations. Using the proposed multiscale methodology for switching peptides, this work will examine sequence effects on phase behavior and morphologies, and elucidate the basic physical interactions that drive their self-assembly.Broader Impacts:This work will develop a fundamental, rigorous new approach to multiscale simulation that will be useful not only for peptides, but for many problems in multiscale physics, offering an important tool for bottom up rational design of nanoscale technologies built on self assembly. For peptides specifically, this work will be the first to couple accurate, converged all atom simulations with multiscale coarse grained ones, and will generate new perspectives on the complex balance of single peptide structure and self assembly driving forces. The prediction of peptide assembly from sequence alone will enable rational peptide design efforts in materials and biology. Work on this project will parallel several educational initiatives. The PI will develop a new graduate molecular simulation elective and online text on molecular thermodynamics that emphasize multiscale physics and leverage peptides as broad examples of self-assembly, solution thermodynamics, polymer physics, nanomaterials, biophysics, and physical chemistry. The PI will continue to use successful research programs at UCSB, such as the Graduate Research Internship Program, to incorporate undergraduates (four so far, including one female)and underrepresented minority students (one summer masters student thus far) in his research. An individual collaboration with a Florida A&M University group will further recruit underrepresented minorities from that institution for summer research in the PI's group. The PI will also continue participation in UCSB's summer undergraduate research seminars and K-12 outreach programs. Finally, the PI will initiate an annual departmental graduate symposium to broaden the reach of research by Ph.D. candidates.