Dynamic Allostery In Proteins

Abstract

Allostery or signalling between two sites of a molecule is a widely present phenomenon in nature. Classically it is believed that the communication between distant sites proceeds via a series of conformational changes. Recently allosteric proteins without conformational change have been observed. This cannot be accounted for with the classical theory and therefore we have built a model that explains the long distance signalling in such cases. We believe that the signalling proceeds via a change in dynamic behaviour of the protein and we illustrate the feasibility of such an explanation on a model system, the Catabolite Activator Protein (CAP).CAP displays negative cooperativity without conformational change upon binding two cAMP ligands. We have built a coarse grain model of multiple slow and fast modes and demonstrated how negative cooperativity can arise without conformational change. The slow, global modes are responsible for the allosteric behavior and result in a purely entropic contribution to the allosteric free energy (ΔΔG). Multiple slow modes need to be included to achieve the experimentally observed free energy values. In the real system compensating entropic and enthalpic terms are observed. Fast modes, despite being localized can couple to the slow modes and assist allostery. We show that they account for the split of ΔΔG into the entropic and enthalpic parts. The value of ΔΔG is proportional to the number of slow modes. The size of the compensating enthalpic and entropic terms increases with number of enslaved fast modes. We can therefore estimate how many slow and fast modes are taking part in the allosteric signaling.