Allosteric Interactions between Proteins on DNA and Membranes

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

The regulation of genes in cells is controlled by the binding/unbinding of proteins on DNA. Often, the binding of one protein changes the binding affinity of a different protein at a distant site on the DNA molecule. This phenomenon is called "allostery"; it has been extensively studied in enzymes, but not through DNA which has mostly been regarded as a rigid object that provides binding sites for proteins. Allostery through DNA has been implicated in many previous experimental studies, including in the binding of drug molecules, but it has not been understood through a mechanical theory which regards DNA as an elastic (not rigid) molecule that is locally deformed by the binding proteins. Similar elastic deformations caused by proteins binding to lipid bilayers also result in allosteric interactions that are responsible for cellular processes, such as, endo- and exo-cytosis required for transport of materials into and out of cells. Often, allostery also involves entropic forces between the proteins that are the result of fluctuations caused by Brownian motion of the elastic media (DNA or lipid membrane) separating them. The overall goal of this research program is to quantitatively describe allosteric interactions between proteins on DNA and lipid membranes through a mathematical theory that regards them as elastic objects while accounting for their Brownian fluctuations. The model will significantly improve understanding of how genes are regulated in living cells. The project will include instruction of graduate students, mentoring of undergraduates and masters students. The PI will also perform outreach through organizing symposia and advanced schools in international conferences, and working with the Penn MRSEC and the Nano Bio Interface Center for NanoDay and other activities targeted at high school (minority) students and teachers. This project will advance the fundamental understanding of allosteric interactions through DNA, thus addressing long-standing open questions in the field and providing quantitative explanations for the wealth of experimental data on the subject. In particular, this project will show how a birod model for DNA can describe the deformations caused by proteins at a single base-pair level, and how the energy due to these deformations is sinusoidally modulated due the helical nature of DNA. For proteins on lipid membranes this project will show how self-assembly may be caused by the competition of their elastic and entropic interactions. The new theoretical approaches developed in this project will enable quantitative predictions of allosteric interactions between proteins as a function of the mechanical properties of the DNA or membrane and the boundary conditions imposed on them by the binding proteins. The analysis performed in this project will place allosteric interactions of proteins on DNA and lipid membranes in the broader context of theories for the interactions of defects in elastic solids.