Book of Abstracts: Albany 2003
June 17-21 2003
From Folding to Function: Lessons of Protein-DNA Interactions
Recognition and binding of specific sites on the DNA by proteins is central for many cellular functions such as transcription, replication, and recombination. In the process of recognition, a protein rapidly searches for its specific site on a long DNA molecule and then strongly binds this site. Here we aim to find a mechanism that provides both (i) fast search (~1 sec) and (ii) high stability of the protein-DNA complex (Kd=1e-15 ...1e-8 M).
Similarly, in protein folding we sought for mechanism that provides both (i) rapid search for the native conformation and (ii) stability of this conformation. These conditions are met in protein folding, by the large energy gap separating folded conformation from the unfolded ones. Unfortunately, such energy gap is not feasible for protein-DNA recognition and we seek for alternative mechanisms.
Earlier studies have suggested that rapid search involves sliding of a protein along the DNA. We consider sliding as a one-dimensional diffusion in rough (random) energy landscape formed by the energy of binding to consecutive sites on the DNA. Our analytical results and computer simulations demonstrate that, in spite of the landscape roughness, rapid search can be achieved by combination of 1D and 3D diffusion. We estimate a narrow range of the specific and non-specific DNA-binding energy required for rapid search. However, realistic energy functions can not provide both rapid search and strong binding. To reconcile these two fundamental requirements we introduce a novel search-binding mechanism that involves coupling of protein binding and protein folding.
Our mechanism is supported by several experimental evidences and known structures of protein-DNA complexes. Our model of protein-DNA recognition suggests new experiments and novel approaches for bioinformatic prediction of DNA-binding sites.
Harvard-MIT Division of Health Sciences and Technology, and Physics