Ranking ligand binding affinities with avidin: a molecular dynamics-based interaction energy study

Wang, Jian; Dixon, R. W.; Kollman, Peter A.

doi:10.1002/(sici)1097-0134(19990101)34:1<69::aid-prot6>3.0.co;2-c

Cited by 100 publications

(125 citation statements)

References 27 publications

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“…This system has been extensively studied most notably by a combination of molecular dynamics, FDPB͞surface area and normal mode analysis (21,37), a hybrid method developed in part to calculate absolute binding constants. Binding is again driven by a strong intermolecular interaction, worth about Ϫ107 kcal͞mol.…”

Section: Resultsmentioning

confidence: 99%

On the calculation of absolute macromolecular binding free energies

Luo

Sharp

2002

Proc. Natl. Acad. Sci. U.S.A.

156

185

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The standard framework for calculating the absolute binding free energy of a macromolecular association reaction A ؉ B 3 AB with an association constant KAB is to equate chemical potentials of the species on the left-and right-hand sides of this reaction and evaluate the chemical potentials from theory. This theory involves (usually hidden) assumptions about what constitutes the bound species, AB, and where the contribution of the solvent appears. We present here an alternative derivation that can be traced back to Bjerrum, in which the expectation value of KAB is obtained directly through the statistical mechanical method of evaluating its ensemble (Boltzmannweighted) average. The generalized Bjerrum approach more clearly delineates: (i) the different contributions to binding; (ii) the origin of the much-discussed and somewhat controversial association entropy term; and (iii) where the solvent contribution appears. This approach also allows approximations required for practical evaluation of the binding constant in complex macromolecular systems, to be introduced in a well defined way. We provide an example, with application to test cases that illustrate a range of binding behavior.T he importance to biochemistry of being able to calculate absolute and relative binding affinities from the structures of macromolecular complexes is clear. A large body of literature on the theory, practice, and application exists. See, for example, refs. 1-8 for recent papers that discuss or review the theory and methods. Nevertheless, there is still controversy over some basic theoretical issues. There is agreement that association is accompanied by a loss of translational and rotational (association) entropy but disagreement over the magnitude, whether it varies significantly from system to system or can be approximated by a single value, what theoretical model should be used to estimate it, and how to include solvent effects. This controversy has motivated recent experimental studies using tethered dimerization to estimate translational entropy loss (9, 10). Accurate accounting of the association term is essential for the calculation of absolute binding free energies. Alternatively, if it could be reliably established by experiment or theory that this term is constant for some set of binding reactions, this would greatly simplify the calculation of relative binding free energies for those systems.The traditional theoretical framework for calculating the absolute binding free energy for the reaction A ϩ B 3 AB is to equate the chemical potentials of the species on the left-and right-hand sides of this reaction and to evaluate the chemical potentials of the three species, A, B, and AB by using some theory, as described in Hill's classic statistical mechanics treatment of association (11). Recent work describes the extension of this approach to macromolecular association and to ligand-membrane association, along with a detailed discussion of other theoretical issues (1, 2). However, the chemical potential approach is not the only ...

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Section: Resultsmentioning

confidence: 99%

On the calculation of absolute macromolecular binding free energies

Luo

Sharp

2002

Proc. Natl. Acad. Sci. U.S.A.

156

185

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“…Especially when dealing with high-resolution protein crystal structures, these methodologies have proven the ability to reproduce with accuracy experimentally measured binding affinities [51][52][53][54]. In the field of GPCRs, a successful attempt to calculate the free energy of binding between the cholecystokinin-1 receptor (CCK1R) and a cholecystokinin peptide composed of nine amino acids (CCK9) was made by performing "alchemical" transformation of the peptide into a mutated one with known affinity for the receptor using FEP in a water-lipid environment [55].…”

Section: Structure-based Methodologiesmentioning

confidence: 99%

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

Costanzi

Tikhonova

Harden

2008

J Comput Aided Mol Des

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SummaryAccurate in silico models for the quantitative prediction of the activity of G protein-coupled receptor (GPCR) ligands would greatly facilitate the process of drug discovery and development. Several methodologies have been developed based on the properties of the ligands, the direct study of the receptor-ligand interactions, or a combination of both approaches. Ligand-based three-dimensional quantitative structure-activity relationships (3D-QSAR) techniques, not requiring knowledge of the receptor structure, have been historically the first to be applied to the prediction of the activity of GPCR ligands. They are generally endowed with robustness and good ranking ability; however they are highly dependent on training sets. Structure-based techniques generally do not provide the level of accuracy necessary to yield meaningful rankings when applied to GPCR homology models. However, they are essentially independent from training sets and have a sufficient level of accuracy to allow an effective discrimination between binders and nonbinders, thus qualifying as viable lead discovery tools. The combination of ligand and structure-based methodologies in the form of receptor-based 3D-QSAR and ligand and structure-based consensus models results in robust and accurate quantitative predictions. The contribution of the structure-based component to these combined approaches is expected to become more substantial and effective in the future, as more sophisticated scoring functions are developed and more detailed structural information on GPCRs is gathered.

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“…The ligands are shown in Figure 1. The avidinbiotin and lysozyme-benzene systems have been the subject of several previous theoretical studies [21,33,34,35,36,37,38,39,40,41,42,43,44,45],…”

Section: Protein and Ligand Preparationsmentioning

confidence: 99%

A comparison of different initialization protocols to obtain statistically independent molecular dynamics simulations

Genheden

Ryde

2010

J Comput Chem

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We study how the results of molecular dynamics (MD) simulations are affected by various choices during the setup, e.g., the starting velocities, the solvation, the location of protons, the conformation of His, Asn, and Gln residues, the protonation and titration of His residues, and the treatment of alternative conformations. We estimate the binding affinity of ligands to four proteins calculated with the MM/GBSA method (molecular mechanics combined with a generalized Born and surface area solvation energy). For avidin and T4 lysozyme, all variations gave similar results within 2 kJ/mol. For factor Xa, differences in the solvation or in the selection of alternative conformations gave results that are significantly different from those of the other approaches by 4–6 kJ/mol, whereas for galectin‐3, changes in the conformations, rotations, and protonation gave results that differed by 10 kJ/mol, but only if residues close to the binding site were modified. This shows that the results of MM/GBSA calculations are reasonably reproducible even if the MD simulations are set up with different software. Moreover, we show that the sampling of phase space can be enhanced by solvating the systems with different equilibrated water boxes, in addition to the common use of different starting velocities. If different conformations are available in the crystal structure, they should also be employed to enhance the sampling. Protonation, ionization, and conformations of Asn, Gln, and His may also be used to enhance sampling, but great effort should be spent to obtain as reliable predictions as possible close to the active site. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011

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Ranking ligand binding affinities with avidin: a molecular dynamics-based interaction energy study

Cited by 100 publications

References 27 publications

On the calculation of absolute macromolecular binding free energies

On the calculation of absolute macromolecular binding free energies

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

A comparison of different initialization protocols to obtain statistically independent molecular dynamics simulations

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