Dependencies of J-Couplings upon Dihedral Angles on Proteins

Salvador, P.

doi:10.1016/b978-0-12-800185-1.00005-x

Cited by 17 publications

(16 citation statements)

References 133 publications

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“…67 ( , ) 3 , ( , ′ ) 3 , and ( , ) 3 were also computed using Karplus equations and backbone dihedral angle values <> and <ψ> sampled from the MSM. 68 Interaction energies between binding site residues (Arg55, Ile57, Phe60, Met61, Gln63, Asn102, Gln111, Phe113, Trp121, Leu122 and His126) and all atoms of the substrate were analysed with the Gromacs g_energy module, using snapshots from the US simulations. The…”

Section: Other Trajectory Analysesmentioning

confidence: 99%

Allosteric effects in catalytic impaired variants of the enzyme cyclophilin A may be explained by changes in nano-microsecond time scale motions

Wapeesittipan

Mey

Walkinshaw

et al. 2017

Preprint

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Abstract:Robust catalyst design requires clear understanding of the mechanisms by which molecular motions influence catalysis. This work investigates the connection between molecular motions and catalysis for the much debated enzyme Cyclophilin A (CypA) in wild-type (WT) form, and a variant that features a distal serine to threonine (S99T) mutation. Previous biophysical studies have proposed that conformational exchange between a 'major' active and a 'minor' inactive state on millisecond timescales plays a key role in catalysis. Here this hypothesis was addressed with molecular dynamics simulation techniques. The simulations reproduce well NMR-derived measurements of changes of activation barriers for the cis/trans amide group isomerization of a model substrate, and support X-ray crystallography derived evidence for a shift in populations of major and minor active site conformations between the wild-type and S99T mutant forms. Strikingly, exchange between major and minor active site conformations occurs at a rate that is 5 to 6 orders of magnitude faster than previously proposed. Further analyses indicate that the decreased catalytic activity of the S99T mutant is a result of weakened hydrogen bonding interactions between the substrate and several active site residues in the transition state ensemble.Weakened hydrogen bonding interactions in the S99T mutant are due to an overall increase in fast positional fluctuations of active site residues caused by poorer packing of sidechains.Therefore the previously described millisecond time scale coupled motions are not necessary to explain allosteric effects in the S99T Cyclophilin A mutant.

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Section: Other Trajectory Analysesmentioning

confidence: 99%

Allosteric effects in catalytic impaired variants of the enzyme cyclophilin A may be explained by changes in nano-microsecond time scale motions

Wapeesittipan

Mey

Walkinshaw

et al. 2017

Preprint

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“…However, measurement of 3 J HN-Hα coupling constants provides additional evidence that the latch residues are undergoing conformational averaging in solution. The 3 J HN-Hα coupling constants can be quantitatively related to the backbone torsion angle φ via a Karplus-type relation [ 91 ], and were measured experimentally for almost all residues in L-BD ( Table S4 ). For residues within the helices of the structured binding domain, variance between the experimentally measured 3 J HN-Hα values, and those calculated from the crystal structure using the Karplus relation is small (RMSD 0.99 Hz; calculations performed for chain A, space group P2 1 ) However, for the residues located in the latch (residues 329–334), the variance between experimental 3 J HN-Hα values and those calculated from the crystal structure is much larger (RMSD 2.53 Hz), supporting a high degree of intra-chain mobility in this region.…”

Section: Resultsmentioning

confidence: 99%

Structural Analysis of the Menangle Virus P Protein Reveals a Soft Boundary between Ordered and Disordered Regions

Webby

Herr

Bulloch

et al. 2021

Viruses

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The paramyxoviral phosphoprotein (P protein) is the non-catalytic subunit of the viral RNA polymerase, and coordinates many of the molecular interactions required for RNA synthesis. All paramyxoviral P proteins oligomerize via a centrally located coiled-coil that is connected to a downstream binding domain by a dynamic linker. The C-terminal region of the P protein coordinates interactions between the catalytic subunit of the polymerase, and the viral nucleocapsid housing the genomic RNA. The inherent flexibility of the linker is believed to facilitate polymerase translocation. Here we report biophysical and structural characterization of the C-terminal region of the P protein from Menangle virus (MenV), a bat-borne paramyxovirus with zoonotic potential. The MenV P protein is tetrameric but can dissociate into dimers at sub-micromolar protein concentrations. The linker is globally disordered and can be modeled effectively as a worm-like chain. However, NMR analysis suggests very weak local preferences for alpha-helical and extended beta conformation exist within the linker. At the interface between the disordered linker and the structured C-terminal binding domain, a gradual disorder-to-order transition occurs, with X-ray crystallographic analysis revealing a dynamic interfacial structure that wraps the surface of the binding domain.

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“…Since considerable changes in the conformation of biomolecules can be captured by variations in the dihedral angles of the molecules ( Salvador, 2014 ; Cukier, 2015 ; Ostermeir and Zacharias, 2014 ; Lemke and Peter, 2019 ), we represent a molecule’s conformation by the cosine and the sine of the dihedral angles ( Mu et al, 2005 ) of that conformation. For these, we make use of the omega (ω), phi (ϕ), psi (ψ), and chi 1 (χ1) dihedral angles (with examples illustrated in Figure 1 ).…”

Section: Methodsmentioning

confidence: 99%

DESP: Deep Enhanced Sampling of Proteins’ Conformation Spaces Using AI-Inspired Biasing Forces

Salawu

2021

Front. Mol. Biosci.

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The molecular structures (i.e., conformation spaces, CS) of bio-macromolecules and the dynamics that molecules exhibit are crucial to the understanding of the basis of many diseases and in the continuous attempts to retarget known drugs/medications, improve the efficacy of existing drugs, or develop novel drugs. These make a better understanding and the exploration of the CS of molecules a research hotspot. While it is generally easy to computationally explore the CS of small molecules (such as peptides and ligands), the exploration of the CS of a larger biomolecule beyond the local energy well and beyond the initial equilibrium structure of the molecule is generally nontrivial and can often be computationally prohibitive for molecules of considerable size. Therefore, research efforts in this area focus on the development of ways that systematically favor the sampling of new conformations while penalizing the resampling of previously sampled conformations. In this work, we present Deep Enhanced Sampling of Proteins’ Conformation Spaces Using AI-Inspired Biasing Forces (DESP), a technique for enhanced sampling that combines molecular dynamics (MD) simulations and deep neural networks (DNNs), in which biasing potentials for guiding the MD simulations are derived from the KL divergence between the DNN-learned latent space vectors of [a] the most recently sampled conformation and those of [b] the previously sampled conformations. Overall, DESP efficiently samples wide CS and outperforms conventional MD simulations as well as accelerated MD simulations. We acknowledge that this is an actively evolving research area, and we continue to further develop the techniques presented here and their derivatives tailored at achieving DNN-enhanced steered MD simulations and DNN-enhanced targeted MD simulations.

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Dependencies of J-Couplings upon Dihedral Angles on Proteins

Cited by 17 publications

References 133 publications

Allosteric effects in catalytic impaired variants of the enzyme cyclophilin A may be explained by changes in nano-microsecond time scale motions

Allosteric effects in catalytic impaired variants of the enzyme cyclophilin A may be explained by changes in nano-microsecond time scale motions

Structural Analysis of the Menangle Virus P Protein Reveals a Soft Boundary between Ordered and Disordered Regions

DESP: Deep Enhanced Sampling of Proteins’ Conformation Spaces Using AI-Inspired Biasing Forces

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