Allosteric control of kinesin's motor domain by tubulin: a molecular dynamics study.

Molecular motors such as kinesin are essential for many biological processes. These motors have two motor domains, which bind to tubulin filaments, hydrolyze ATP, and transduce the released chemical energy into directed movements. The general principles of this chemomechanical coupling are now well-established but the underlying molecular mechanisms remain elusive because small conformational changes within large proteins are difficult to detect experimentally. Here, we use atomistic molecular dynamics simulations to monitor such changes within a single motor domain of KIF1A, which belongs to the kinesin-3 motor family. The nucleotide binding pocket of this domain can be empty or occupied by ATP or ADP. For these three nucleotide states, we determine the mobility of the backbone of the protein, both in solution and attached to tubulin. Only one subdomain of the motor domain is found to exhibit a strongly increased mobility upon binding to tubulin: the neck linker that presumably acts as a mechanical transmitter to the other motor domain in dimeric kinesin-3 motors. Furthermore, upon binding to tubulin, the neck linker mobility becomes sensitive to the bound nucleotide and is highly increased after phosphate release, which implies undocking of this linker from the core of the motor domain. These simulation results are consistent with experimental data from EPR spectroscopy, FRET, and cryo-electron microscopy. A detailed analysis of our simulation data also reveals that the undocking of the neck linker in the ADP-kinesin-tubulin state arises from allosteric interactions between the nucleotide and tubulin and that the ß-sheet core undergoes a twist both during phosphate release and ATP binding. The computational approach used here can be applied to other motor domains and mechanoenzymes in order to identify allosteric interactions between the subdomains of these proteins.

Ion dynamics and water percolation effects in DNA polymorphism.

The dynamics of ions and water at the surface of DNA are studied by computer simulations in a wide range of hydrations involving the zone of low-hydration polymorphism in DNA. The long-range mobility of ions exhibits a stepwise increase at three distinct hydration levels. The first of them is close to the midpoint of the water percolation transition as well as the midpoint of the transition between A- and B-DNA forms. It coincides with the onset of the dissociation of ion pairs on the DNA surface probably caused by the increase in the water dielectric permittivity due to the appearance of the spanning hydrogen-bonding network. The other two steps are attributed to the formation of percolating water layers on the surface of DNA accompanied by the progressive escape of ions from the DNA surface. The results agree with earlier experimental data and further corroborate the suggested universal mechanism of the low hydration polymorphism in DNA including intraduplex electrostatic condensation close to the water percolation threshold.

Temperature-induced conformational transition of a model elastin-like peptide GVG(VPGVG)(3) in water.

The conformation of a single elastin-like peptide GVG(VPGVG)3 in liquid water is studied by computer simulations in the temperature interval between 280 and 440 K. Two main conformational states of the peptide can be distinguished: a rigid conformational state, dominating at low temperatures, and a flexible conformational state, dominating at high temperatures. A temperature-induced transition between these states occurs at about 310 K, rather close to a transition temperature seen in experiments. This transition is accompanied by the thermal breaking of the hydrogen-bonded spanning network of the hydration water via a percolation transition upon heating. This finding indicates that the H-bond clustering structure of the hydration water plays an important role in the conformational stability of biomolecules. A second important observation is the Gaussian distribution of the end-to-end distance in the high-temperature state, which supports the idea of a rubber-like elasticity of the studied elastin-like peptide. Finally our results challenge the idea of the folding of elastin-like peptides upon heating.

Water clustering and percolation in low hydration DNA shells.

The hydrogen-bonded networks of water at the surface of a model DNA molecule are analyzed. At low hydrations, only small water clusters are attached to the DNA surface, whereas, at high hydrations, it is homogeneously covered by a spanning water network. The spanning water network is formed via a percolation transition at an intermediate hydration number of about 15 water molecules per nucleotide, which is very close to the midpoint of polymorphic transitions between A- and B-forms of the double helix. The percolation transition can occur in both A- and B-DNA hydration shells with nearly identical percolation thresholds. However, the mechanism of the percolation transition in A- and B-DNA is qualitatively different in regard to the roles played by the two opposite grooves of the double helix. Free ions can shift the percolation threshold by preventing some water molecules from hydrogen bond networking. The results corroborate the suggested relationship between water percolation and the low hydration polymorphism in DNA.

Water percolation governs polymorphic transitions and conductivity of DNA.

We report on the first computer simulation studies of the percolation transition of water at the surface of the DNA double helix. With increased hydration, the ensemble of small clusters merges into a spanning water network via a quasi-two-dimensional percolation transition. This transition occurs strikingly close to the hydration level where the B form of DNA becomes stable in experiment. Formation of spanning water networks results in sigmoidlike acceleration of long-range ion transport in good agreement with experiment.

Percolation transition of hydration water: from planar hydrophilic surfaces to proteins.

The formation of a spanning hydrogen-bonded network of hydration water is found to occur via a 2D percolation transition in various systems: smooth hydrophilic surfaces, the surface of a single protein molecule, protein powder, and diluted peptide solution. The average number of water-water hydrogen bonds at the percolation threshold varies from 2.0 to 2.3, depending on temperature, system size, and surface properties. Calculation of nH allows an easy estimation of the percolation threshold of hydration water in various systems, including biomolecules.