William Wimley Research Interests

Introduction

The membranes that define and compartmentalize all living cells have been called a "fluid mosaic" of proteins embedded within a lipid bilayer membrane. The integrity of these membranes as well as the functions of the proteins within them are essential to life. For example, more than 25% of all proteins in the human genome are membrane proteins and about half of all drug targets are membrane proteins. Our laboratory is studying the structure and folding of proteins in membranes using peptide model systems and computer analysis. We are also developing methods for the design and engineering of membrane proteins and for the design of molecules that modulate the function or activity of membrane proteins.

The laboratory's broad, long-term research areas are listed below:

Peptide Drug Design

Targeted application of high throughput screening of peptide libraries to problems of acute biomedical interest. e.g. design of peptide antibiotics.

Protein Engineering

Design and engineer peptide model systems that fold into specific structures in membranes. Most of our current efforts are directed toward the design of transmembrane b-barrels.

Physical Chemistry and Thermodynamics

Understand the fundamental physical principles of peptide folding in membranes.

Genomics and Proteomics

Develop algorithms for identifying membrane proteins in genome databases and test those predictions using proteomics methods.

Combinatorial Chemistry & High Throughput Screening

Use combinatorial peptide libraries and high thoughput screening methods to design peptides that fold into specific structures in membranes and to design peptides that specifically interact with particular membrane proteins.

Figures & Sidebars

Techniques Routinely Used in the Laboratory

Solid-phase peptide synthesis

High Pressure Liquid Chromatography

Fluorescence Spectroscopy

Fluorescence Resonance Engergy Transfer

Equilibrium Binding Measurements

Circular Dichroism Spectroscopy

Differential Scanning Calormetry

Isothermal Titration Calorimetry

Combinatorial Peptide Synthesis

High throughput screening

Major Research Equipment

SLM-Aminco 8100 Fluorescence Spectrometer

JASCO 810 Circular Dichroism Spectrometer

Microcal VP-DSC differential scanning calorimeter

Microcal VP-ITC isothermal titration calorimeter

Waters High Pressure Liquid Chromatography System

Applied Biosystems Pioneer Multiple Peptide Synthesizier

The Laboratory's Research Methods

We address protein folding in membranes through the chemical and biophysical study of peptide model systems designed specifically to address one or more of the four conceptual steps (see "Conceptual Model " ) that we use to think about protein folding in membranes: polypeptide binding to membrane surfaces, formation of secondary structure, insertion of secondary structure elements into the membrane and formation of tertiary structure within the membrane. We design and engineer peptide systems iteratively on the basis of both experimental and theoretical work. We use standard solid-phase peptide synthesis and combinatorial peptide synthesis to make peptides, and we use biophysical methods such as fluorescence, circular dichroism, equilibrium binding and calorimetry to characterize the binding, structure, and peptide organization within membranes.

Sources of Laboratory Funding Laboratory Personnel

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