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• The Open State Gating Mechanism of Gramicidin A Requires Rel...

  The Open State Gating Mechanism of Gramicidin A Requires Relative Opposed Monomer Rotation and Simultaneous Lateral Displacement Structure, Volume 14, Issue 8, 1 August 2006, Pages 1241-1249 Gennady V. Miloshevsky and Peter C. Jordan Summary The gating mechanism of the open state of the gramicidin A (gA) channel is studied by using a new Monte Carlo Normal Mode Following (MC-NMF) technique, one applicable even without a target structure. The results demonstrate that the lowest-frequency normal mode (NM) at ∼6.5 cm is the crucial mode that initiates dissociation. Perturbing the gA dimer in either direction along this NM leads to opposed, nearly rigid-body rotations of the gA monomers around the central pore axis. Tracking this NM by using the eigenvector-following technique reveals the channel's gating mechanism: dissociation via relative opposed monomer rotation and simultaneous lateral displacement. System evolution along the lowest-frequency eigenvector shows that the large-amplitude motions required for gating (dissociation) are not simple relative rigid-body motions of the monomers. Gating involves coupling intermonomer hydrogen bond breaking, backbone realignment, and relative monomer tilt with complex side chain reorganization at the intermonomer junction. Summary | Full Text | PDF (418 kb)

• Analysis of Functional Motions in Brownian Molecular Machine...

  Analysis of Functional Motions in Brownian Molecular Machines with an Efficient Block Normal Mode Approach: Myosin-II and Ca-ATPase Biophysical Journal, Volume 86, Issue 2, 1 February 2004, Pages 743-763 Guohui Li and Qiang Cui Abstract The structural flexibilities of two molecular machines, myosin and Ca-ATPase, have been analyzed with normal mode analysis and discussed in the context of their energy conversion functions. The normal mode analysis with physical intermolecular interactions was made possible by an improved implementation of the block normal mode (BNM) approach. The BNM results clearly illustrated that the large-scale conformational transitions implicated in the functional cycles of the two motor systems can be largely captured with a small number of low-frequency normal modes. Therefore, the results support the idea that structural flexibility is an essential part of the construction principle of molecular motors through evolution. Such a feature is expected to be more prevalent in motor proteins than in simpler systems (e.g., signal transduction proteins) because in the former, large-scale conformational transitions often have to occur before the chemical events (e.g., ATP hydrolysis in myosin and ATP binding/phosphorylation in Ca-ATPase). This highlights the importance of Brownian motions associated with the protein domains that are involved in the functional transitions; in this sense, Brownian molecular machines is an appropriate description of molecular motors, although the normal mode results do not address the origin of the ratchet effect. The results also suggest that it might be more appropriate to describe functional transitions in some molecular motors as intrinsic elastic motions modulating local structural changes in the active site, which in turn gets stabilized by the subsequent chemical events, in contrast with the conventional idea of local changes somehow getting amplified into larger-scale motions. In the case of myosin, for example, we favor the idea that Brownian motions associated with the flexible converter propagates to the Switch I/II region, where the salt-bridge formation gets stabilized by ATP hydrolysis, in contrast with the textbook notion that ATP hydrolysis drives the converter motion. Another useful aspect of the BNM results is that selected low-frequency normal modes have been identified to form a set of collective coordinates that can be used to characterize the progress of a significant fraction of large-scale conformational transitions. Therefore, the present normal mode analysis has provided a stepping-stone toward more elaborate microscopic simulations for addressing critical issues in free energy conversions in molecular machines, such as the coupling and the causal relationship between collective motions and essential local changes at the catalytic active site where ATP hydrolysis occurs. Abstract | Full Text | PDF (1356 kb)

• Stability of Triple-Helical Poly(dT)-Poly(dA)-Poly(dT) DNA w...

  Stability of Triple-Helical Poly(dT)-Poly(dA)-Poly(dT) DNA with Counterions Biophysical Journal, Volume 75, Issue 1, 1 July 1998, Pages 70-91 Voichita M. Dadarlat and V.K. Saxena Abstract Structural conformation of triple-helical poly(dT)-poly(dA)-poly(dT) has been a very controversial issue recently. Earlier investigations, based on fiber diffraction data and molecular modeling, indicated an A-form conformation with sugar pucker. On the other hand, Raman, solution infrared spectral, and NMR studies show a B-form structure with sugars. In accordance with these experimental results, a theoretical model with B-form, sugars was proposed in 1993. In the present work we investigate the dynamics and stability of the two conformations within the effective local field approach applied to the normal mode calculations for the system. The presence of counterions was explicitly taken into account. Stable equilibrium positions for the counterions were calculated by analyzing the normal mode dynamics and free energy of the system. The breathing modes of the triple helix are shifted to higher frequencies over those of the double helix by 4–16cm. The characteristic marker band for the B conformation at 835cm is split up into two marker bands at 830 and 835cm. A detailed comparison of the normal modes and the free energies indicates that the B-form structure, with sugar pucker, is more stable than the A-form structure. The normal modes and the corresponding dipole moments are found to be in close agreement with recent spectroscopic findings. Abstract | Full Text | PDF (307 kb)

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Abstract

We display the displacement vectors or eigenvectors of calculations of the A- and B-DNA backbones. These calculations are based on a refinement scheme that simultaneously fit several backbone modes of A-DNA, B-DNA, and A-RNA. We discuss the role of symmetry operations in mode calculations and the relevance of these displacement vectors to the interpretation of linear dichroism measurements performed on the A- and B-DNA helix.