A method for computing low-frequency normal modes of large symmetric assemblies of macromolecules : Application to the disk of tobacco mosaic virus protein

Enzymologie physicochimique, F-91405 Orsay, France.

Abstract

A general method for studying the dynamics of large protein multimers, which combines elementary group theory with protein molecular dynamics is presented. This method explicitly includes the long-range correlations between protein subunits. It is thus designed to address directly collective dynamic effects, such as coo- perativity between subunits. The method is in no way limited to vacuum simulations, nor even to the harmonic approximation. Indeed it can be combined with minor modification and additional programming with the quasi-harmonic molecular dynamics approach, which includes solvent effects and low-order anharmonic effects. For cyclic point groups (C_n), the method has been incorporated into the program CHARMM; the additional programming for the other point groups would be reasonably straightforward. It is applied to a harmonic and scaled-harmonic simulation of the disk of tobacco mosaic virus (TMV) coat protein, in vacuo. The system has over 66000 degrees of freedom, yet the calculation is reduced by symmetry to a problem of order 3900.

The disk of protein is a likely candidate for direct involvement in the assembly of tobacco mosaic virus, binding to a specific sequence of viral RNA to initiate growth of the viral particle. The initial binding is known to be cooperative, involving six protein subunits. It has been suggested that binding of RNA might decrease the activation energy for dislocation of the disk, which would in turn accelerate the growth of the virus. Such an effect would imply that the RNA perturbs significantly the dynamics of the protein disk. The most likely vehicle for such a perturbation would be electrostatic interactions, because of their long range. We have therefore investigated the fluctuations of the whole disk, and their coupling to RNA-like charges. This coupling is measured by the dipolar susceptibility of the disk in response to discrete charges.