Biology subjects

Kennedy, S. D.

Publications and source records attributed to Kennedy, S. D..

3 recordsLinked to original sources

bioRxiv2025

NMR and molecular dynamics demonstrate the RNA internal loop GAGU is dynamic and adjacent base pairs determine conformational preference

The conformational variability of RNA duplexes with the internal loop 5GAGU/3UGAG was investigated by a combination of nuclear magnetic resonance spectroscopy (NMR) and all-atom molecular dynamics (MD) simulations. A previous study showed that the CG-flanked internal loop in the sequence 5GACGAGUGUCA/3ACUGUGAGCAG existed in a major conformation (conformation I) characterized by Uridines U7 and U7* bulging into solution, A5 and A5* stacking, and with G4-G6* and G6-G4* base pairs closing the loop on either end. It was also determined that a minor conformation existed with a set of closing G-U pairs with a bifurcated hydrogen bond and A-G non-canonical pairs with a single hydrogen bond (conformation II). A maximum hydrogen bonding structure with wobble G-U pairs and A-G pairs with two hydrogen bonds (conformation III) was not observed by NMR or predicted by molecular dynamics. In this work, alternative flanking base pairs A-U, U-A and G-C were studied by substituting the C-G base pair adjacent to the GAGU internal loop. NMR spectra demonstrated changes in conformational preference depending on the identity of the flanking pair. Clustering analyses of structures from MD simulations of C-G- and U-A-flanked duplexes showed transitions between minor conformations II and III with a greater fraction of the structures in conformation II, in spite of the simulations starting in conformation III. In addition, U-A-flanked simulations contained a substantial amount (25%) of structures in an intermediate state between conformations II and III. A-U- and G-C-flanked structures were all in a single cluster whose centroid structure was in conformation II. MD simulations showed a dominance of structure II over structure III, in agreement with NMR data for C-G closure, but in contrast with the NMR data for other closures. Simulations starting in conformation I did not transition to either of II and III, with all structures being in a single cluster for all flanking base pairs except for G-C-closure where 22% of the structures were in a state defined by a C3endo sugar pucker for G4 and G4*. Bases G4 and G4* were also in syn orientation around the glycosidic bond for all flanking pairs while G6 and G6* transitioned between syn and anti orientations for C-G- and A-U-flanked simulations, consistent with NMR observations.

biophysics↗

bioRxiv2018

Stiffness as a control factor for object manipulation

We act on the world by producing forces that move objects. During manipulation, force is exerted with the expectation that an object will move in an intended manner. This prediction is a learned coordination between force and displacement. Mechanically, impedance is a way to describe this coordination. As an efficient control strategy, object interaction could be anticipated by setting impedance before the hand moves the object. We examined this possibility with a paradigm in which subjects moved a handle to a specific target position along a track. The handle was locked in place until the subject exerted enough force to cross a specific threshold; then the handle was abruptly released and could move along the track. We hypothesized that this ballistic-release task would encourage subjects to modify their arm impedance in anticipation of the upcoming movement. If we consider the handle as an object, this paradigm loosely approximates the uncertainty encountered at the end of a reach when contacting a fixed object. We found that one component of arm impedance, stiffness, varied in a way that matched the behavioral demands of the task and we were able to dissociate stiffness from changes in force and displacement. We also found separate components of muscle activity that corresponded to stiffness and to changes in force. Our results show that subjects used a robust and efficient strategy to coordinate force and displacement by modulating muscle activity in a way that was behaviorally relevant in the task.\n\nNew & NoteworthyThe arm can behave like a spring, suggesting the concept of exerting force to move an object by selecting a spring of a certain length and stiffness that, respectively, depend on the movement and force requirements of the task. We show that these spring-like characteristics describe the strategy used to arrest a pre-loaded handle. These results extend our understanding of the arms spring-like behavior to include force and movement constraints, important factors for object interaction.

neuroscience↗

bioRxiv2017

Conformational Ensemble of RNA Oligonucleotides from Reweighted Molecular Simulations

We determine the conformational ensemble of four RNA tetranucleotides by using available nuclear magnetic spectroscopy data in conjunction with extensive atomistic molecular dynamics simulations. This combination is achieved by applying a reweighting scheme based on the maximum entropy principle. We provide a quantitative estimate for the population of different conformational states by considering different NMR parameters, including distances derived from nuclear Overhauser effect intensities and scalar coupling constants. We show the usefulness of the method as a general tool for studying the conformational dynamics of flexible biomolecules as well as for detecting inaccuracies in molecular dynamics force fields.

biophysics↗