David Worcester

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Associate Professor Emeritus of Biological Sciences

PhD, 1971 Harvard University

Research Summary

Structure and dynamics of biological membranes and membrane components

Research Description

Neutron diffraction is being used to study structure and dynamics of membranes and membrane components. Phospholipids and Phospholipid/cholesterol mixtures are studied using lamellar diffraction and deuterium labeling. We prepare samples as highly oriented multi-layers of about 1000 membranes on quartz substrates, hydrated by relative humidity control. Some phospholipid samples are studied in the crystalline state using diffraction to 1.8Å resolution. Other samples are measured in more fluid/disordered states, as in biological membranes.

Neutron diffraction measurements were made at MURR and more recently as part of a new project at the National Institute of Standards and Technology (NIST) Center for Neutron Research (NCNR) in Gaithersburg, Maryland. The project is Cold Neutrons for Biology and Technology (CNBT), a bioengineering research partnership funded by the National Institute of Health. The CNBT project constructed and now operates a new instrument, the Advanced Neutron Diffractometer/ Reflectometer (AND/R), to investigate structures of membranes and membrane proteins. See http://www.ncnr.nist.gov/programs/reflect/cnbt/. We are involved with several projects using this instrument, including a study of the S1-S4 voltage sensor domain of a potassium channel protein incorporated into phosphatidylcholine/ phosphatidylglycerol multilayer membranes. Measurements of the M2 ion channel of influenza virus are also being made.

Other projects are the nature of hydrocarbon chain ordering by cholesterol and the molecular basis for the preferential interaction of cholesterol with saturated hydrocarbon chain phospholipids. This interaction is apparently responsible for “raft” formation in mixed lipid systems. We are also studying raft formation by in-plane neutron scattering from mixed lipids sandwiched between quartz plates. In these samples, some of the lipids are fully deuterium labeled to provide high contrast between the different lipid regions.

In another project, properties of cadherin proteins are being assessed by sequence analysis and molecular modeling. The cadherin superfamily includes classical cadherins involved in cell adhesion and also many unusual cadherins now recognized to be involved in diverse cellular processes such as planar cell polarity, growth control and opening of ion channels in auditory signal transduction. In our lab, the doctoral research of Nancy Vosnidou used computational quantum chemistry to examine cooperativity in calcium binding in cadherin proteins. This work shows the relative binding affinities of the different calcium ions and explains why calcium is often coordinated by seven oxygen atoms. Cadherin dimerization was examined by sequence analysis and molecular modeling. Several dimerization possibilities were found, suggesting that cadherin interactions are more diverse than is usually thought. These would be important in the interactions of the unusual cadherins, such as dachsous, fat and flamingo.

Selected Publications