Impact of Ligand and Protein Desolvation on Ligand Binding to the S1 Pocket of Thrombin

Biela, Adam; Khayat, Maan T.; Tan, Hongwei; Kong, Jia; Heine, A.; Hangauer, David; Klebe, G.

doi:10.1016/j.jmb.2012.01.054

Cited by 40 publications

(48 citation statements)

References 47 publications

(47 reference statements)

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“…Often this reflected binding of the ligands on the surface of their proteins, allowing the ligand to grow into unfilled areas of the site and solvent (35)(36)(37)(38)(39). In the case of FabI, the enzyme responds to a series of six side-chain elongations of diphenyl ethers with a smooth shift of Ile207 and 0.5-0.9 Å movements of Tyr147 and Val201 (40) (SI Appendix, Fig.…”

Section: Conformations In Other Lysozyme Cavities Recapitulate the Threementioning

confidence: 99%

Homologous ligands accommodated by discrete conformations of a buried cavity

Merski

Fischer

Balius

et al. 2015

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

114

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Conformational change in protein–ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-methylene increases from benzene to n-hexylbenzene, bound to an enclosed cavity in T4 lysozyme. The volume of the apo cavity suffices to accommodate benzene but, even with toluene, larger cavity conformations become observable in the electron density, and over the series two other major conformations are observed. These involve discrete changes in main-chain conformation, expanding the site; few continuous changes in the site are observed. In most structures, two discrete protein conformations are observed simultaneously, and energetic considerations suggest that these conformations are low in energy relative to the ground state. An analysis of 121 lysozyme cavity structures in the PDB finds that these three conformations dominate the previously determined structures, largely modeled in a single conformation. An investigation of the few congeneric series in the PDB suggests that discrete changes are common adaptations to a series of growing ligands. The discrete, but relatively few, conformational states observed here, and their energetic accessibility, may have implications for anticipating protein conformational change in ligand design.

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Section: Conformations In Other Lysozyme Cavities Recapitulate the Threementioning

confidence: 99%

Homologous ligands accommodated by discrete conformations of a buried cavity

Merski

Fischer

Balius

et al. 2015

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

114

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“…Whereas we could predict if the change in ligand structure should lead to an increase or decrease in binding free energies, quantitatively predicting the exact ΔΔ G bind value with chemical accuracy remains challenging, implying that dissecting the various terms contributing to a change in binding affinity is difficult, and determining the exact quantitative effect of water molecules still needs improvement in the field. Recent thermodynamic studies on congeneric thrombin inhibitors showed that in the context of water displacement, small changes in ligand structures can lead to dramatic changes in thermodynamic signatures . This points out that lead optimization guided by water thermodynamics is difficult, and that most approaches presented in the literature are too simplistic for quantitative predictions.…”

Section: Discussionmentioning

confidence: 99%

“…Recent thermodynamic studies on congeneric thrombin inhibitors showed that in the context of water displacement,s mall changes in ligand structures can lead to dramaticc hanges in thermodynamic signatures. [38,39] This points out that lead optimizationg uided by water thermodynamics is difficult, and that most approaches presented in the literature [6,12,13,18] are too simplistic for quantitative predictions.Ap rediction of ac hange in bindingf ree energy upon scaffold minimization can be feasible if the dominating terms are only the changei ni nteraction energy and change in solvation free energy.H owever,o ur examples showed that this is not even given for highly congeneric ligandsw ith the same bindingm ode and only minor structuraldifferences.…”

Section: Discussionmentioning

confidence: 99%

Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations

Wahl

Smieško

2018

ChemMedChem

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Computational methods, namely molecular dynamics (MD) simulations in combination with inhomogeneous fluid solvation theory (IFST) were used to retrospectively investigate various cases of ligand structure modifications that led to the displacement of binding site water molecules. Our findings are that water displacement per se is energetically unfavorable in the discussed examples, and that it is merely the fine balance between change in protein-ligand interaction energy, ligand solvation free energies, and binding site solvation free energies that determine if water displacement is favorable or not. We furthermore evaluated if we can reproduce experimental binding affinities by a computational approach combining changes in solvation free energies with changes in protein-ligand interaction energies and entropies. In two of the seven cases, this estimation led to large errors, implying that accurate predictions of relative binding free energies based on solvent thermodynamics is challenging. Nevertheless, MD simulations can provide insight regarding which water molecules can be targeted for displacement.

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“…The protease thrombin is known to bind sodium natively (Di Cera et al, 1995) and has previously been used as a model system for ion identification based on valence calculations of solvent atoms (Nayal & Di Cera, 1996). We examined a set of ten ligand-bound structures (Biela et al, 2012) determined at near-atomic resolution (between 1.27 and 1.90 Å ), which we have used for testing automated ligandplacement and refinement (Echols et al, 2014), Each of these has two sodium ions modeled in the deposited structure, one internal and one bound by crystal contacts, both present at full occupancy with excellent density and coordination shells. For these tests the process was started from the original molecularreplacement search model without ligands; the structures were solved and refined automatically to within 2% of the final R free values.…”

Section: Application To Lighter Cationsmentioning

confidence: 99%