TITLE:

DOES MOLECULAR MOTION MATTER FOR PROTEIN FUNCTION?

DATE:

Friday, April 11th, 2008

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

John Love, Department of Chemistry and Biochemistry, San Diego State University

ABSTRACT:

The correlation between protein structure and function is well established yet the role flexibility/stability plays in protein function is still being explored. In the Love laboratory we employ protein design methodologies to explore (and measure) the correlation between flexibility/stability and protein function. Overall we use computational and experimental approaches to explore three related areas in the field of protein design.

1) The role intrinsic flexibility/stability plays in protein function.

2) Methods and screens designed to increase the intrinsic stability of proteins.

3) The de novo design of novel protein/protein interactions.

For the project in which we are exploring the role flexibility/stability plays in protein function we are utilizing a well-characterized protein/DNA interaction (i.e., the LEF-1 HMG domain bound to cognate DNA). NMR analysis of the LEF-1 DNA binding domain in complex with DNA revealed that the protein is quite well-ordered while bound to its consensus sequence. On the other hand the free LEF-1 domain exhibits considerable structural instability and conformational heterogeneity. This behavior raises the following questions: Why does the free DNA binding domain exhibit such significant disorder? Could the flexibility be necessary for the gross perturbations that occur within the DNA upon binding? Is this behavior functionally essential for DNA bending? What impact would the introduction of stability have on the protein’s function? For that matter, is it possible to introduce stability? These questions, along with our attempts to answer them will be described. In addition to the above I will also describe our ongoing efforts to develop in vivo screens for protein stability using rational design in combination with computational methods. Finally I will discuss our goal of using computational and experimental methods to engineer proteins that bind and inactivate important physiological targets.

HOST:

Andy Cooksy

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