Book of Abstracts: Albany 2007
June 19-23 2007
General Transfer Matrix Formalism to Calculate DNA-Protein Binding in Gene Regulation: Applications to the Lambda-Switch and Beyond
The transfer matrix methodology is proposed as a systematic tool for statistical-mechanical description of DNA-protein binding involved in gene regulation. Having started from the classical matrix approaches for simple systems such as DNA melting and DNA-ligand binding (e.g., Crothers, 1968), we end up with a new paradigm applicable to the complex gene regulatory events. We show that a genetic system consisting of several cis-regulatory modules is computable using the matrix method, considering explicitly site-overlapping, competitive, cooperative binding of regulatory proteins, their multilayer assembly, DNA bending and looping. We systematically derive matrix models for the basic types of short- and long-range interactions between DNA-bound proteins, drugs and nucleosomes, and the enhanceosome formation.
The Figure below shows an example of the application of our method to gene regulation at OR operator of phage lambda. Here, the transfer matrix formalism allowed a description of the lambda-switch at a single-nucleotide resolution, taking into account the effects of range of interprotein distances. Our calculations confirm the previously established roles of the contact interactions between regulatory proteins CI and Cro and RNA polymerase (RNAP). Concerning long-range interactions, we show that while the DNA loop between OR and OL operators is important at the lysogenic CI concentrations, the interference between the adjacent promoters PR and PRM becomes more important at very small CI concentrations. In particular, Figure B shows that up to 20% change of the expression pattern may arise in this regime due to anticooperative interactions between DNA-bound RNAP?s (see solid vs. dashed lines). The applicability of the transfer matrix formalism to more complex genetic systems will be discussed.
This work was supported by BFFI, grant # B06M-127.
Vladimir B. Teif
Institute of Bioorganic Chemistry