Topological Analysis of Proteins as Derived from Medium and High‐resolution Electron Density: Applications to Electrostatic Properties

Leherte, Laurence; Guillot, Benoı̂t; Vercauteren, Daniel P.; Pichon‐Pesme, Virginie; Jelsch, Christian; Lagoutte, A.; Lecomte, Claude

doi:10.1002/9783527610709.ch11

Cited by 9 publications

(12 citation statements)

References 41 publications

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“…To directly link MEP and experimental ED distribution functions, one could use databases of transferable multipolar ED parameters for evaluating atom charges, as presented by Zarichta et al 72 and preliminarly applied to the human aldose reductase system, 36 and then calculate MEP functions. …”

Section: Discussionmentioning

confidence: 99%

Coarse Point Charge Models For Proteins From Smoothed Molecular Electrostatic Potentials

Leherte

Vercauteren

2009

J. Chem. Theory Comput.

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To generate coarse electrostatic models of proteins, we developed an original approach to hierarchically locate maxima and minima in smoothed molecular electrostatic potentials. A charge-fitting program was used to assign charges to the so-obtained reduced representations. Templates are defined to easily generate coarse point charge models for protein structures, in the particular cases of the Amber99 and Gromos43A1 force fields. Applications to four small peptides and to the ion channel KcsA are presented. Electrostatic potential values generated by the reduced models are compared with the corresponding values obtained using the original sets of atomic charges.

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Section: Discussionmentioning

confidence: 99%

Coarse Point Charge Models For Proteins From Smoothed Molecular Electrostatic Potentials

Leherte

Vercauteren

2009

J. Chem. Theory Comput.

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“…As a result, the determination of very accurate electron density maps from x-ray crystallography has become accessible to numerous research laboratories in the world. QTAIM, having its starting point the electron density, has quickly acquired the status of the single most important theory used to analyze experimental density maps nowadays [30,31,[120][121][122][123][124][125][126][127]. Experimental densities are currently analyzed by several software, we mention among them XD [128] and MOPRO [129,130] as examples.…”

Section: Future Perspectivementioning

confidence: 99%

Electron-Density Descriptors as Predictors in Quantitative Structure–Activity/Property Relationships and Drug Design

Matta

Arabi

2011

Future Med. Chem.

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The use of electron density-based molecular descriptors in drug research, particularly in quantitative structure--activity relationships/quantitative structure--property relationships studies, is reviewed. The exposition starts by a discussion of molecular similarity and transferability in terms of the underlying electron density, which leads to a qualitative introduction to the quantum theory of atoms in molecules (QTAIM). The starting point of QTAIM is the topological analysis of the molecular electron-density distributions to extract atomic and bond properties that characterize every atom and bond in the molecule. These atomic and bond properties have considerable potential as bases for the construction of robust quantitative structure--activity/property relationships models as shown by selected examples in this review. QTAIM is applicable to the electron density calculated from quantum-chemical calculations and/or that obtained from ultra-high resolution x-ray diffraction experiments followed by nonspherical refinement. Atomic and bond properties are introduced followed by examples of application of each of these two families of descriptors. The review ends with a study whereby the molecular electrostatic potential, uniquely determined by the density, is used in conjunction with atomic properties to elucidate the reasons for the biological similarity of bioisosteres.

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“…[3,4] Besides the use of unit charges as in references, [5 -9] an approach to assign a partial charge to a molecular fragment or to the corresponding pseudo-atom, named here coarse grain, is to sum over the atomic charges involved in the fragment. [10,11] In the work of DeVane et al [9], unit values are scaled down to compensate for the solvent that is represented by uncharged spheres. Advanced approaches involve the assignment of multipolar contributions to ellipsoids.…”

Section: Introductionmentioning

confidence: 99%

Reduced point charge models of proteins: assessment based on molecular dynamics simulations

Leherte

2015

Molecular Simulation

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A reduced point charge distribution is used to model Ubiquitin and two complexes, Vps27 UIM-1 -Ubiquitin and BarnaseBarstar. It is designed from local extrema in charge density distributions obtained from the Poisson equation applied to smoothed molecular electrostatic potentials. A variant distribution is built by locating point charges on atoms. Various charge fitting conditions are selected, i.e. from either electrostatic Amber99 (Assisted Model Building with Energy Refinement) Coulomb potential or forces, considering reference grid points located within various distances from the protein atoms, with or without separate treatment of main and side chain charges. The program GROMACS (Groningen Machine for Chemical Simulations) is used to generate Amber99SB molecular dynamics (MD) trajectories of the solvated proteins modelled using the various reduced point charge models (RPCMs) so obtained. Point charges that are not located on atoms are considered as virtual sites. Some RPCMs lead to stable MD trajectories. They, however, involve a partial loss in the protein secondary structure and lead to a less-structured solute solvation shell. The model built by fitting charges on Coulomb forces calculated at grid points ranging between 1.4 and 2.0 times the van der Waals radius of the atoms, with a separate treatment of main chain and side chain charges, appears to best approximate all-atom MD trajectories.

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Topological Analysis of Proteins as Derived from Medium and High‐resolution Electron Density: Applications to Electrostatic Properties

Cited by 9 publications

References 41 publications

Coarse Point Charge Models For Proteins From Smoothed Molecular Electrostatic Potentials

Coarse Point Charge Models For Proteins From Smoothed Molecular Electrostatic Potentials

Electron-Density Descriptors as Predictors in Quantitative Structure–Activity/Property Relationships and Drug Design

Reduced point charge models of proteins: assessment based on molecular dynamics simulations

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