Functional modes of proteins are among the most robust ones

It is shown that a small subset of modes which are likely to be involved in protein functional motions of large amplitude can be determined by retaining the most robust normal modes obtained using different protein models. This result should prove helpful in the context of several applications proposed recently, like for solving difficult molecular replacement problems or for fitting atomic structures into low-resolution electron density maps. Moreover, it may also pave the way for the development of methods allowing to predict such motions accurately.Comment: 4 pages, 5 figure

Glassy Dynamics of Protein Folding

A coarse grained model of a random polypeptide chain, with only discrete torsional degrees of freedom and Hookean springs connecting pairs of hydrophobic residues is shown to display stretched exponential relaxation under Metropolis dynamics at low temperatures with the exponent $\beta\simeq 1/4$, in agreement with the best experimental results. The time dependent correlation functions for fluctuations about the native state, computed in the Gaussian approximation for real proteins, have also been found to have the same functional form. Our results indicate that the energy landscape exhibits universal features over a very large range of energies and is relatively independent of the specific dynamics.Comment: RevTeX, 4 pages, multicolumn, including 5 figures; larger computations performed, error bars improve

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 yield an approximation of strongly nonlinear dynamics.Comment: 10 pages, 6 figure

On the origin of the Boson peak in globular proteins

We study the Boson Peak phenomenology experimentally observed in globular proteins by means of elastic network models. These models are suitable for an analytic treatment in the framework of Euclidean Random Matrix theory, whose predictions can be numerically tested on real proteins structures. We find that the emergence of the Boson Peak is strictly related to an intrinsic mechanical instability of the protein, in close similarity to what is thought to happen in glasses. The biological implications of this conclusion are also discussed by focusing on a representative case study.Comment: Proceedings of the X International Workshop on Disordered Systems, Molveno (2006

Universal behavior of localization of residue fluctuations in globular proteins

Localization properties of residue fluctuations in globular proteins are studied theoretically by using the Gaussian network model. Participation ratio for each residue fluctuation mode is calculated. It is found that the relationship between participation ratio and frequency is similar for all globular proteins, indicating a universal behavior in spite of their different size, shape, and architecture.Comment: 4 pages, 3 figures. To appear in Phys. Rev.

The ves hypothesis and protein misfolding

Proteins function by changing conformation. These conformational changes, which involve the concerted motion of a large number of atoms are classical events but, in many cases, the triggers are quantum mechani- cal events such as chemical reactions. Here the initial quantum states after the chemical reaction are assumed to be vibrational excited states, something that has been designated as the VES hypothesis. While the dynamics under classical force fields fail to explain the relatively lower structural stability of the proteins associated with misfolding diseases, the application of the VES hy- pothesis to two cases can provide a new explanation for this phenomenon. This explanation relies on the transfer of vibrational energy from water molecules to proteins, a process whose viability is also examined

The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page