Nonlinearity of Mechanochemical Motions in Motor Proteins

The assumption of linear response of protein molecules to thermal noise or structural perturbations, such as ligand binding or detachment, is broadly used in the studies of protein dynamics. Conformational motions in proteins are traditionally analyzed in terms of normal modes and experimental data on thermal fluctuations in such macromolecules is also usually interpreted in terms of the excitation of normal modes. We have chosen two important protein motors — myosin V and kinesin KIF1A — and performed numerical investigations of their conformational relaxation properties within the coarse-grained elastic network approximation. We have found that the linearity assumption is deficient for ligand-induced conformational motions and can even be violated for characteristic thermal fluctuations. The deficiency is particularly pronounced in KIF1A where the normal mode description fails completely in describing functional mechanochemical motions. These results indicate that important assumptions of the theory of protein dynamics may need to be reconsidered. Neither a single normal mode nor a superposition of such modes yields an approximation of strongly nonlinear dynamics.Author Summary: Biological cells use a variety of molecular machines representing enzymes, ion channels or pumps, and motors. Motor proteins are nanometer-size devices generating forces and actively moving or rotating under the supply of chemical energy through ATP hydrolysis. They are crucial for many cell functions and promising for nanotechnology of the future. Although such motors represent single molecules, their operation cycles cannot be followed in detail in simulations even on the best modern supercomputers and some approximations need to be employed. It is often assumed that conformational dynamics of motor proteins is well described within a linear response approximation and corresponds to excitation of normal modes. We have checked this assumption for two motor proteins, myosin V and kinesin KIF1A. Our results show that, while both these biomolecules respond by well-defined motions to energetic excitations, these motions are essentially nonlinear. The effect is particularly pronounced in KIF1A where relaxation proceeds through a sequence of qualitatively different conformational changes, which may facilitate complex functional motions without additional control mechanisms.