scholarly journals Conformational Ensemble of RNA Oligonucleotides from Reweighted Molecular Simulations

2017 ◽  
Author(s):  
Sandro Bottaro ◽  
Giovanni Bussi ◽  
Scott D. Kennedy ◽  
Douglas H. Turner ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Molecular Dynamics ◽  
Nuclear Overhauser Effect ◽  
Conformational Dynamics ◽  
Maximum Entropy Principle ◽  
Coupling Constants ◽  
Scalar Coupling ◽  
Conformational Ensemble ◽  
Entropy Principle ◽  
Nuclear Overhauser ◽  
Dynamics 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.

scholarly journals Accuracy in determining interproton distances using Nuclear Overhauser Effect data from a flexible molecule

2011 ◽  
Vol 7 ◽  
pp. 145-150 ◽  
Author(s):  
Catharine R Jones ◽  
Craig P Butts ◽  
Jeremy N Harvey
Keyword(s):  
Nuclear Overhauser Effect ◽  
Coupling Constants ◽  
Scalar Coupling ◽  
Dynamical Analysis ◽  
Flexible Molecules ◽  
Large Numbers ◽  
Distance Restraints ◽  
Nuclear Overhauser ◽  
Interproton Distances

The determination of accurate NOE-derived interproton distances and confirmation/prediction of relative populations in multi-conformer, flexible small molecules was investigated with the model compound 4-propylaniline. The low accuracy assumed for semi-quantitative NOE distance restraints is typically taken to suggest that large numbers of constraints need to be used in the dynamical analysis of flexible molecules, and this requires, for example, the measurement and Karplus-type analysis of scalar coupling constants (3 J CH and 3 J HH). Herein we demonstrate that, contrary to this common perception, NOE measurements alone are accurate enough to establish interproton distances, and hence conformational detail, in flexible molecules to within a few percent of their ensemble-averaged values, hence reducing the demand for additional restraints in such dynamic analyses.

scholarly journals Conformational ensembles of an RNA hairpin using molecular dynamics and sparse NMR data

2019 ◽  
Vol 48 (3) ◽  
pp. 1164-1174 ◽  
Author(s):  
Sabine Reißer ◽  
Silvia Zucchelli ◽  
Stefano Gustincich ◽  
Giovanni Bussi
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Structural Information ◽  
Nuclear Overhauser Effect ◽  
Protein Translation ◽  
Aqueous Environment ◽  
Rna Dynamics ◽  
Nuclear Overhauser ◽  
Dynamics Simulations ◽  
Solution Nuclear Magnetic Resonance

Abstract Solution nuclear magnetic resonance (NMR) experiments allow RNA dynamics to be determined in an aqueous environment. However, when a limited number of peaks are assigned, it is difficult to obtain structural information. We here show a protocol based on the combination of experimental data (Nuclear Overhauser Effect, NOE) and molecular dynamics simulations with enhanced sampling methods. This protocol allows to (a) obtain a maximum entropy ensemble compatible with NMR restraints and (b) obtain a minimal set of metastable conformations compatible with the experimental data (maximum parsimony). The method is applied to a hairpin of 29 nt from an inverted SINEB2, which is part of the SINEUP family and has been shown to enhance protein translation. A clustering procedure is introduced where the annotation of base-base interactions and glycosidic bond angles is used as a metric. By reweighting the contributions of the clusters, minimal sets of four conformations could be found which are compatible with the experimental data. A motif search on the structural database showed that some identified low-population states are present in experimental structures of other RNA transcripts. The introduced method can be applied to characterize RNA dynamics in systems where a limited amount of NMR information is available.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

Schistosomal Sulfotransferase Interaction with Oxamniquine Involves Hybrid Mechanism of Induced-fit and Conformational Selection

2020 ◽  
Vol 16 (4) ◽  
pp. 451-459 ◽  
Author(s):  
Fortunatus C. Ezebuo ◽  
Ikemefuna C. Uzochukwu
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Binding Energy ◽  
Binding Site ◽  
Conformational Dynamics ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Conformational Selection ◽  
Hybrid Mechanism ◽  
Dynamics Simulations

Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards activation of oxamniquine has not received attention. Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine activation by schistosomal sulfotransferase using molecular dynamics simulations and binding energy calculations. Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA. Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase sampled different conformational space involving several rotameric states. Importantly, Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium of its conformational distribution. In addition, the result showed binding energy of -130.091 ± 8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol. Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase engineering and design of new drugs that target sulfotransferase.

scholarly journals NMR solution conformation of heparin-derived tetrasaccharide

1996 ◽  
Vol 318 (1) ◽  
pp. 93-102 ◽  
Author(s):  
Dmitri MIKHAILOV ◽  
Kevin H. MAYO ◽  
Ioncho R. VLAHOV ◽  
Toshihiko TOIDA ◽  
Azra PERVIN ◽  
...  
Keyword(s):  
Chair Conformation ◽  
Coupling Constants ◽  
Solution Conformation ◽  
1H And 13C Nmr ◽  
Small Deviations ◽  
J Coupling Constants ◽  
Nuclear Overhauser ◽  
Nuclear Overhauser Effects ◽  
Dynamics Simulations ◽  
Ring Conformations

The solution conformation of the homogeneous, heparin-derived tetrasaccharide ΔUA2S(1 → 4)-α-d-GlcNpS6S(1 → 4)-α-l-IdoAp2S(1 → 4)-α-d-GlcNpS6S (residues A, B, C and D respectively, where IdoA is iduronic acid) has been investigated by using 1H- and 13C-NMR. Ring conformations have been defined by J-coupling constants and inter-proton nuclear Overhauser effects (NOEs), and the orientation of one ring with respect to the other has been defined by inter-ring NOEs. NOE-based conformational modelling has been done by using the iterative relaxation matrix approach (IRMA), restrained molecular dynamics simulations and energy minimization to refine structures and to distinguish between minor structural differences and equilibria between various ring forms. Both glucosamine residues B and D are in the 4C1 chair conformation. The 6-O-sulphate group is oriented in the gauche–trans configuration in the D ring, whereas in the B ring the gauche–gauche rotomer predominates. Uronate (A) and iduronate (C) residues are mostly represented by 1H2 and 2S0 twisted boat forms, respectively, with small deviations in expected coupling constants and NOEs suggesting minor contributions from other A and C ring conformations.

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