Absolute Binding Free Energy Calculations of Sparsomycin Analogs to the Bacterial Ribosome

Ge, Xiaoxia; Roux, Benoı̂t

doi:10.1021/jp100579y

Cited by 50 publications

(49 citation statements)

References 86 publications

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“…Other examples of pathway free-energy techniques are steered MD (58) and umbrella sampling (59), and other methods in which the ligand/target interactions are gradually switched off. Among these techniques are thermodynamic integration (60), free-energy perturbation (FEP) (61–63), double decoupling method (64), and double annihilation method (65, 66). At variance with the latter techniques, in FM information about the ligand binding mode is not required in advance, although the approximate location of the binding site in the target structure should be known.…”

Section: Discussionmentioning

confidence: 99%

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Moraca

Amato

Ortuso

et al. 2017

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

106

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SignificanceA thorough characterization of the binding interaction between a drug and its molecular target is fundamental to successfully lead drug design. We demonstrate that this characterization is also possible using the recently developed method of funnel-metadynamics (FM), here applied to investigate the binding of berberine to DNA G-quadruplex. We computed a quantitatively well-characterized free-energy landscape that allows identifying two low-energy ligand binding modes and the presence of higher energy prebinding states. We validated the accuracy of our calculations by steady-state fluorescence experiments. The good agreement between the theoretical and experimental binding free-energy value demonstrates that FM is a most reliable method to study ligand/DNA interaction.

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Section: Discussionmentioning

confidence: 99%

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Moraca

Amato

Ortuso

et al. 2017

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

106

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“…52–55 and was previously applied to T4 Lysozyme, 54 FKBP12, 53 and the bacterial ribosome. 56, 57 The approach was recently extended by a global replica-exchange molecular dynamics scheme with respect of the thermodynamic coupling parameters “λ” implemented in the program CHARMM version c36a6 43 via the parallel-parallel REPDSTR 58–61 module. 60, 61 We refer to this method as FEP/λ-REMD simulations.…”

Section: Computational Detailsmentioning

confidence: 99%

Computational Analysis of the Binding Specificity of Gleevec to Abl, c-Kit, Lck, and c-Src Tyrosine Kinases

Lin

Roux

2013

J. Am. Chem. Soc.

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Gleevec, a well-known cancer therapeutic agent, is an effective inhibitor of several tyrosine kinases, including Abl and c-Kit. But it displays less potency to inhibit closely homologous tyrosine kinases, such as Lck and c-Src. Because many structural features of the binding site are highly conserved in these highly homologous kinases, the molecular determinants responsible for the binding specificity of Gleevec remain poorly understood. To address this issue, free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent was used to compute the binding affinity of Gleevec to Abl, c-Kit, Lck, and c-Src. The results of the FEP/MD calculations are in good agreement with experiments, enabling a detailed and quantitative dissection of the absolute binding free energy in terms of various thermodynamic contributions affecting the binding specificity of Gleevec to the kinases. Dominant binding free energy contributions arises from the van der Waals dispersive interaction, compensating about two-third of the unfavorable free energy penalty associated with the loss of translational, rotational, and conformational freedom of the ligand upon binding. In contrast, the contributions from electrostatic and repulsive interactions nearly cancel out due to solvent effects. Furthermore, the calculations show the importance of the conformation of the activation loop. Among the kinases examined, Abl provides the most favorable binding environment for Gleevec via optimal protein-ligand interactions and a small free energy cost for loss of the translational, rotational, and conformational freedom upon ligand binding. The FEP/MD calculations additionally reveal that Lck and c-Src provide similar non-binding interactions with the bound-Gleevec, but the former pays less entropic penalty for the ligand losing its translational, rotational, and conformational motions to bind, examining the empirically observed differential binding affinities of Gleevec between the two Src-family kinases.

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“…Useful prediction of ligand binding affinities is still challenging. 151,163,44,40,126,113,73,153,147,154 …”

Section: Introductionmentioning

confidence: 99%

Protonation and pK changes in protein–ligand binding

Onufriev

Alexov

2013

Quart. Rev. Biophys.

165

161

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Formation of protein-ligand complexes causes various changes in both the receptor and the ligand. This review focuses on changes in pK and protonation states of ionizable groups that accompany protein-ligand binding. Physical origins of these effects are outlined, followed by a brief overview of the computational methods to predict them and the associated corrections to receptor-ligand binding affinities. Statistical prevalence, magnitude, and spatial distribution of the pK and protonation state changes in protein-ligand binding are discussed in detail, based on both experimental and theoretical studies. While there is no doubt that these changes occur, they do not occur all the time; the estimated prevalence varies, both between individual complexes and by method. The changes occur not only in the immediate vicinity of the interface, but sometimes far away. When receptor-ligand binding is associated with protonation state change at particular pH, the binding becomes pH dependent: we review the interplay between sub-cellular characteristic pH and optimum pH of receptor-ligand binding. It is pointed out that there is a tendency for protonation state changes upon binding to be minimal at physiologically relevant pH for each complex (no net proton uptake/release), suggesting that native receptor-ligand interactions evolved to reduce the energy cost associated with ionization changes. As a result, previously reported statistical prevalence of these changes – typically computed at the same pH for all complexes – may be higher than what may be expected at optimum pH specific to each complex. We also discuss whether proper account of protonation state changes appears to improve practical docking and scoring outcomes relevant to structure-based drug design. An overview of some of the existing challenges in the field is provided in conclusion.

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Absolute Binding Free Energy Calculations of Sparsomycin Analogs to the Bacterial Ribosome

Cited by 50 publications

References 86 publications

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Computational Analysis of the Binding Specificity of Gleevec to Abl, c-Kit, Lck, and c-Src Tyrosine Kinases

Protonation and pK changes in protein–ligand binding

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