David A. Brant - US grants

This project is designed to investigate the relationships between chemical structure and the solution conformation of complex carbohydrate polymers, such as those that occur at eucaryotic cell surfaces, in the connective tissue of the higher organisms, and in the extrcellular capsules and slimes of various microorganisms. Attention will be focussed on the extracellular microbial polysaccharides, many of which are immunogenic and essential for microbial infection of the host organisms. Quantitative measurements of various macromolecular solution properties will be carried out. In particular, spatial and geometric features accessible directly from light scattering and high resolution nuclear magnetic resonance experiments will be investigated. These characteristics are also calculable quantitatively from detailed and realistic molecular models using theoretical methods of conformational analysis and statistical mechanics. Agreement between observed and calculated results can engender confidence in the physical reality of the molecular models employed. Reliable polysaccharide chain models may be used, often in conjunction with computer graphics techniques, to understand the structure-conformation relationships in general and to identify the energetically preferred conformations of the complex carbohydrate polymers. Such conformational information is essential to an understanding of the intermolecular interactions that mediate the biological function of many of these materials.

This project uses the methods of physical chemistry to investigate the equilibrium distribution of energetically preferred conformations of carbohydrate polymers and oligomers and the rates and mechanisms by which these molecules pass from one conformation to another. Oligo- and polysaccharides play an important part in the biological processes of cellular recognition, signaling, and adhesion. Bacterial capsular polysaccharides, for example, frequently elicit an immune response in the host organism and, hence, have potential uses in the production of vaccines against pathogenic organisms. The capacity of carbohydrate macromolecules for diversity of structure and conformation makes them ideal candidates for roles in the storage and expression of biological information at the surfaces of biological cells. A full understanding of these processes demands a appreciation of the process by which a particular primary sequence of sugars expresses its conformational preferences, the interactions which stabilize the preferred conformations, and the processes and pathways by which these large molecules pass from one conformation to another among the various molecular shapes in the equilibrium distribution. In this project several structurally simple polymers of glucose are investigated by means of NMR relaxation and dynamic rheology to probe their rates of motion on the nanosecond and microsecond time scales. These experiments are complemented by a theoretical analysis designed to interpret the observable dynamic properties on a molecular basis. Such studies probe the fundamental processes of intramolecular motion that may occur as a carbohydrate ligand interacts with a protein receptor. The structure and stability of multiple-stranded helical structures in two classes of microbial polysaccharides are investigated using such techniques as NMR spectroscopy, electron and scanning probe microscopy, light scattering, scanning calorimetry, and conformational modeling. These studies are designed to elucidate the nature and strength of the solvent- modulated carbohydrate-carbohydrate interactions that determine carbohydrate conformation in aqueous media. Such carbohydrate-carbohydrate interactions may also be involved in certain biological recognition processes.

Support for a new workstation cluster is requested to meet the computing needs of nine NIH-funded faculty and their research groups in the Department of Chemistry at UCI. The cluster consists of a multi- processor server and six Silicon Graphics O2 R1200 workstations with molecular modeling software. NIH-supported research projects for which the requested computing resources is needed are: 1) Structural modeling of biopolymers and model systems: Modeling the structure and dynamics of polysaccharides; design of new phosphatase inhibitors through active-site modeling and library searching; predicting and understanding the structure of artificial beta-sheets; modeling structure and dynamics of pulmonary surfactant proteins. The last is a new hire who does not yet have NIH support. 2) Prediction of organic reactivity and selectivity: Design of a variety of new stereoselective reactions; synthesis of complex natural products and other targets of biological and pharmaceutical interest. The number and breadth of the NIH-supported research projects described herein are large. While most of the researchers are primarily experimentalists, significant computational work is a key component of all of these projects. Researchers rely on a centralized facility for most effective utilization of CPU and graphics resources among a large number of researchers who are primarily experimentalists and thus intermittent users, and for cost savings. A significant multi-processor computer will allow larger scale calculations currently inaccessible to us. The strong Chemistry theory group at UCI, a Molecular Modeling Facility Manger who is a Ph.D. chemist with computational chemistry expertise, and a commitment to training graduate researchers in modeling methods who have made our existing shared computing resources extremely valuable. Existing hardware is becoming obsolete and new hardware has become an urgent need. UCI has made a significant long-term funding commitment to excellence in computational chemistry research and instructions through the salary of the Facility Manager.

Through FOCUS (Faculty Outreach Collaborations Uniting Scientists, Students and Schools), the University of California, Irvine (UCI) unites the efforts of mathematics, science, education and research library faculty and staff with educators from local community colleges, school districts and local educational support agencies. The partnership builds on prior established relationships between UCI and three high-need California school districts: Compton Unified, Santa Ana Unified and the Westside of Newport-Mesa Unified. These schools serve 106,695 students of whom 82% are Hispanic and 11% are African American.

The work of FOCUS will include the construction of a "future teacher highway" to increase the number, quality and diversity of preK-12 teachers of mathematics and science; involvement of math and science professionals in "Discipline Dialogues" that cross segmental boundaries, and the creation of systemic reform in the professional development of preK-12 teachers of mathematics and science. FOCUS will ultimately impact the number of new mathematics and science teachers; the number of high school students prepared for and enrolled in advanced mathematics and science coursework; the achievement gap between the general student population and English Language Learners; and the number of higher education faculty engaged in efforts with preK-12 educational systems.

A collaboration between the University of California, Irvine (UCI) Schools of Physical and Biological Sciences, the UCI Department of Education, four regional school districts, and two regional community colleges is providing the necessary infrastructure to recruit, train, and provide professional support for future mathematics and science teachers preparing to teach in high-need school districts in the Orange County, California region. The UCI Noyce Scholarship Program builds on the infrastructure provided by a UCI Math and Science Partnership project to provide a comprehensive continuum of teacher preparation programs and strategies that achieve objectives for teacher recruitment, preparation for teaching success, and nurturing a commitment to teaching in a high-need district. Approximately fifty three one-year scholarships are being awarded over a four year period to: a) prospective secondary math and science teachers who are UCI STEM majors in their senior and final undergraduate year, and b) single subject math and science preservice teacher candidates enrolled in the UCI fifth-year credential program. At least two senior year scholarships per year are identified for UCI STEM majors who have transferred to UCI from a partner community college. Scholarship recipients fulfill their teaching commitment in partner schools districts where they have had previous apprentice teaching experiences, and where they benefit from new teacher induction programs and professional development opportunities. The program is developing strategies and conditions for preparing and nurturing STEM majors for success in secondary teaching in high-need regional school districts with diverse student populations. One strategy is to provide a continuum of coherently linked preparation and professional support experiences, in pre-credential, credential and induction phases, that develop subject matter and pedagogic knowledge, teacher growth through reflective inquiry, and leadership potential. Another strategy is to create collaborations between the university, regional community colleges, and regional high-need school districts, in order to provide a continuum of experiences to develop aspiring teachers' knowledge about and commitment to a school district and its community, teachers, and diverse student population. Undergraduate baccalaureate programs in mathematics and the sciences, combined with state-approved undergraduate subject matter preparation programs, provide the foundation of subject matter knowledge that is critical for the teaching success of scholarship recipients. Similarly, the UCI undergraduate educational studies minor and the Teacher Credential Program provide the necessary foundations of pedagogical knowledge and practice that scholarship recipients need.