A quantitative measure and molecular-level interpretation of protein-lipid interactions is essential to understand the partitioning, folding and function of membrane-proteins, which make up 20-30% of the human genome. Furthermore, understanding the physical rules that govern the assembly of membranes with their associated proteins is important for future developments in integrated biomembrane nano-devices. Experiment has provided a wealth of valuable information about protein-membrane interaction. Modern computer simulation can complement these experiments, strengthen our microscopic understanding and resolve some unanswered questions. A rigorous statistical mechanical framework is invoked here to capture the free energies governing protein structure and function in a membrane environment. These free energy calculations will push the boundaries of state of the art simulation. Despite the challenges, Dr. Allen has devised a realizable strategy employing polypeptides as model transmembrane segments to elucidate the general mechanisms of protein-lipid interaction. To begin, microscopic simulations will provide a free energy profile of an amino acid, attached to a transmembrane segment, and reveal bilayer perturbations as a function of depth. Such information is unattainable with experiment, yet essential to understand how the stability of a membrane-protein is determined by the specific arrangement of amino acids in the three-dimensional protein structure. The principle of 'hydrophobic matching' has been used to help explain the insertion and folding of proteins, protein activity, lipid micro-domain formation and protein aggregation. Dr. Allen details a series of new and innovative umbrella sampling and free energy perturbation calculations that directly tackle the thermodynamics governing mismatch.
Dr. Allen's dedication to university and community is evidenced by his contributions and innovations in teaching and outreach activities. A revamped Computational Chemistry course will tie in both Dr. Allen's previous teaching and current research so that students, theoretical or experimental, learn the skills needed to pursue projects and critically assess published results. Dr. Allen is actively seeking new and exciting ways of harnessing the curiosity and enthusiasm of young and underprivileged students and encouraging them to pursue careers in science. He will co-organize and mentor in the ACS 'SEED' program at UCD which is designed to create opportunities for high school students from economically disadvantaged backgrounds. He is working with the COSMOS program (http://cosmos.ucdavis.edu) to develop a 4-week course suitable for high-school students and is also developing his own initiative, 'Careers in Chemical and Biological Simulation', that will bring together scientists from university and industry to provide students with exciting opportunities in chemical and biological simulation.
Intellectual Merit: A quantitative measure and molecular-level interpretation of protein-lipid interactions is essential to understand the partitioning, folding and function of membrane-proteins, which make up 20-30% of the human genome and over 70% of all drug targets. In this award, a rigorous statistical mechanical framework was invoked to capture the free energies governing protein structure and conformational changes in a membrane environment, and to determine what controls the movements of charged molecules and amino acids within and across membranes. This work has helped to resolve controversies and has challenged prevailing views in the field of protein-lipid interactions. This project revealed that the membrane is not a uniform hydrophobic slab, but perturbs significantly due to the presence of the positively charged ions and amino acid side chains, with water and lipid head groups penetrating into the membrane. This work uncovered unexpected properties of cell membranes for improved understanding of protein function and the actions of viruses, toxins and antimicrobial peptides. The project also explored the ability of aromatic side-chains to anchor proteins in membranes, and carried out extensive simulations to understand the mechanisms of hydrophobic matching that controls the insertion and folding of proteins and protein activity. This work led to high impact publications, including first-tier journals such as the Proceedings of the National Academy of Sciences and rated by the Biology Faculty of 1000 as ‘must read’, ‘technical advance’, ‘prediction’, ‘controversial’ and ‘new finding’. A total of 13 manuscripts were published that acknowledge this award (with several others in preparation) and this work has been presented on over 75 occasions. Broad Impact: All of the educational and outreach initiatives outlined in the proposal have been implemented. Prof. Allen has created an educational framework for the future of biomolecular simulation science at UC Davis and beyond. He has been active in seeking new and exciting ways of harnessing the curiosity and enthusiasm of young and underprivileged students and encouraging them to pursue careers in science. Prof. Allen mentored 13 graduate students and postdocs and hosted several other rotation, undergraduate and high school students as a result of this award. His students published high impact papers, won prizes, poster competitions and scholarships. His undergraduate and graduate classes all had excellent evaluations and he taught students the basic skills to pursue careers in computational chemistry, biology and drug design. Among other contributions, he created, organized and taught in an annual, month-long COSMOS program for high-school students to learn chemistry with applications in computation and biology. He created the program SYLICCO "SYmposium on Learning and Industry targeting Computational Chemistry Opportunities", that brought together leading scientists for the benefit of students who wish to pursue careers in computational chemistry and biophysics. He also taught in the "Explorit" non-profit outreach organization, bringing science to those who would not otherwise have access. Prof. Allen’s commitment to enhancing the UCD environment for outreach education is illustrated by these and other contributions which have taken his NSF-funded science to the grass roots of the community to provide students with opportunities in chemical and biological simulation.
