Mechanical Model of DNA Allostery.

The importance of allosteric effects in DNA is becoming increasingly appreciated, but the underlying mechanisms remain poorly understood. In this work, we propose a general modeling framework to study DNA allostery. We describe DNA in a coarse-grained manner by intra-base pair and base pair step coordinates, complemented by groove widths. Quadratic deformation energy is assumed, yielding linear relations between the constraints and their effect. Model parameters are inferred from standard unrestrained, explicit-solvent molecular dynamics simulations of naked DNA. We applied the approach to study minor groove binding of diamidines and pyrrole-imidazole polyamides. The predicted DNA bending is in quantitative agreement with experiment and suggests that diamidine binding to the alternating TA sequence brings the DNA closer to the A-tract conformation, with potentially important functional consequences. The approach can be readily applied to other allosteric effects in DNA and generalized to model allostery in various molecular systems.