Communicating helices: molecular simulation of allosteric receptor proteins

The interaction of a cell with its environment occurs at the cell membrane. Typically, binding of a signal ligand to a protein receptor introduces a change in the receptor that propagates to the cytoplasmic end of the receptor, causing binding or release of a second ligand. Such long-distance propagation through the receptor is referred to as the allosteric effect. We investigate the allosteric mechanism of bacterial chemoreceptors via all-atom Molecular Dynamics of the HAMP domains - the signal conversion module of the receptors. Our simulations show that the prototype HAMP Af1503 is relatively stable and exhibits rigid body motions of its helices in the piston and tilting mode. However, in a polyHAMP system consisting of consecutive HAMPs, such rigid body motions, though exist, are uncorrelated among different HAMPs. Moreover, the HAMP domain from the serine receptor Tsr is highly dynamic: the signaling mechanism of Tsr-HAMP could involve changes in the degree of the helical characters and in the fluctuations of its key hydrophobic side-chains. We also investigate the signaling mechanism of G-Protein-Coupled-Receptors (GPCRs) via a simple coarse-grained model. Our results indicate that signaling via a GPCR can occur through merely the rigid body fluctuations of its helices without a change in its average conformation.