Conformational sensitivity of polyether macrocycles to electrostatic potential: Partial atomic charges, molecular mechanics, and conformational prediction

Shirts, Randall B.; Stolworthy, Lloyd D.

doi:10.1007/bf00708876

Cited by 18 publications

(8 citation statements)

References 89 publications

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“…Shirts and Stolworthy [295] analysis of a crown ether (18-crown-6) showed that the electrostatic term is the largest contributor to the conformational energy and discussed the desirability of using a polarizable method, such as the charge equilibration algorithms, to include these effects in MM and MD calculations. During development of the FQ method by Berne and co-workers investigations of the aqueous solvation and reoganization energy of other molecules, notably formaldehyde, were performed [296,297].…”

Section: Application Of Polarizable Force Fieldsmentioning

confidence: 99%

Molecular modeling and dynamics studies with explicit inclusion of electronic polarizability: theory and applications

2009

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A current emphasis in empirical force fields is on the development of potential functions that explicitly treat electronic polarizability. In the present article, the commonly used methodologies for modelling electronic polarization are presented along with an overview of selected application studies. Models presented include induced point-dipoles, classical Drude oscillators, and fluctuating charge methods. The theoretical background of each method is followed by an introduction to extended Langrangian integrators required for computationally tractable molecular dynamics simulations using polarizable force fields. The remainder of the review focuses on application studies using these methods. Emphasis is placed on water models, for which numerous examples exist, with a more thorough discussion presented on the recently published models associated with the Drudebased CHARMM and the AMOEBA force fields. The utility of polarizable models for the study of ion solvation is then presented followed by an overview of studies of small molecules (e.g. CCl 4 , alkanes, etc) and macromolecule (proteins, nucleic acids and lipid bilayers) application studies. The review is written with the goal of providing a general overview of the current status of the field and to facilitate future application and developments.

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Section: Application Of Polarizable Force Fieldsmentioning

confidence: 99%

Molecular modeling and dynamics studies with explicit inclusion of electronic polarizability: theory and applications

2009

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“…Thus, we have performed standard MM/GBSA calculations for the seven biotin analogues with either the correct QM charges for each snapshot or with the other charge sets. To investigate the distance dependence of the effect, we have also used mixed charge sets, where the charges of all residues outside a certain distance from the ligand (we used 16 different distances, 3,5,7,9,11,13,15,17,19,21,23,25,27,30,35, and 40 Å for the charged biotin analogues and 2, 3,4,5,6,7,8,9,10,12,15,20,25,30,35, and 40 Å for the others) are changed to the approximate charges.…”

Section: Solvent-screened Interaction Energiesmentioning

confidence: 99%

Conformational dependence of charges in protein simulations

Söderhjelm¹,

Ryde²

2008

J Comput Chem

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We have studied the conformational dependence of molecular mechanics atomic charges for proteins by calculating the charges fitted to the quantum mechanical (QM) electrostatic potential (ESP) for all atoms in complexes between avidin and seven biotin analogues for 20 snapshots from molecular dynamics simulations. We have studied how various other charge sets reproduce those charges. The QM charges, even if averaged over all snapshots or all residues, in general have a larger magnitude than standard Amber charges, indicating that the restraint toward zero in the restrained ESP method is too strong. This has a significant influence on the electrostatic conformational energies and the interaction energy between the biotin ligand and the protein, giving a difference between the QM and Amber charges of 43 and 8 kJ/mol for the negatively charged and neutral biotin analogues, respectively (3-4%). However, this energy difference is strongly reduced if the solvation energy (calculated by the Poisson-Boltzmann or Generalized Born methods) is added, viz., to 7 kJ/mol for charged and 3 kJ/mol for uncharged ligand. In fact, charges need to be recalculated with a QM method only for residues within 7 or 4 A of the ligand, if the error should be less than 4 kJ/mol. Unfortunately, the QM charges do not give significantly better MM/PBSA estimates of ligand-binding affinities than standard Amber charges.

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“…First, charges on atoms that are buried by the other atoms are poorly determined, meaning that they may become unphysically large and that different charges may give fits of a similar quality1, 2. Second, it is well‐known that ESP charges depend quite strongly on the conformation of the molecule6–10. Several methods have been suggested to cure these problems, e.g., by fixing some charges11, fitting to several conformations simultaneously12, 13, fitting to the ESP of one conformation with restraints to the dipole moment of another molecule12, restraining the charges toward zero13–15, (or to Mulliken or other less conformational‐dependent charges16, 17), or averaging the charges obtained for different conformations18.…”

Section: Introductionmentioning

confidence: 99%

Transferability of conformational dependent charges from protein simulations

Genheden

Söderhjelm

Ryde

2011

Int J of Quantum Chemistry

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We have studied the transferability of atomic charges for proteins, fitted to the quantum mechanical electrostatic potential and extensively averaged over a set of structures sampled by molecular dynamics (MD) and over all residue of the same kind in the protein sequence (xAvESP). Previously, such charges were obtained for one single protein (avidin). In this study, we employ five additional proteins. The aim of this study is fourfold. First, we provide xAvESP charges for all amino acids, including amino-and carboxy-terminal variants of all, as well as alternative protonation states of His, Asp, Glu, Lys, Arg, Cys, and Tyr. Second, we show that the xAvESP charges averaged over the five new proteins are similar to charges obtained in the same way for avidin, with a correlation coefficient of 0.997. This shows that the charges are transferable and system-independent. Electrostatic protein-ligand interaction energies calculated with charges obtained from different proteins differ by only 1-3 kJ/mol on average. The xAvESP charges correlate rather well with Amber charges (except for the N atom of amino-terminal residues), although they are obtained in a more general way. Third, the conformational dependence of the charges is significant and gives rise to quite large differences in energies. However, these differences are to a large extent screened by solvation effects. For example, the solvent-screened electrostatic interaction energy between the protein galectin-3 and five different ligands varies with the charge sets by less than 3 kJ/mol on average. Finally, we show that the xAvESP charges give a comparable root-mean-squared deviation as the Amber charges for the MD simulations of 18 protein-ligand complexes, they give comparable or slightly worse backbone N-H order parameters for two galectin-3 complexes, but they give a better correlation between calculated and experimental affinities for the binding of seven biotin analogues to avidin and for nine inhibitors of factor Xa.

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Conformational sensitivity of polyether macrocycles to electrostatic potential: Partial atomic charges, molecular mechanics, and conformational prediction

Cited by 18 publications

References 89 publications

Molecular modeling and dynamics studies with explicit inclusion of electronic polarizability: theory and applications

Molecular modeling and dynamics studies with explicit inclusion of electronic polarizability: theory and applications

Conformational dependence of charges in protein simulations

Transferability of conformational dependent charges from protein simulations

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