3qtv Citations

Impact of ligand and protein desolvation on ligand binding to the S1 pocket of thrombin.

J Mol Biol 418 350-66 (2012)
Related entries: 3p17, 3qto, 3qwc, 3qx5, 3sha, 3shc, 3si3, 3si4, 3sv2

Cited: 15 times
EuropePMC logo PMID: 22366545

Abstract

In the present study, we investigate the impact of a tightly bound water molecule on ligand binding in the S1 pocket of thrombin. The S1 pocket contains a deeply buried deprotonated aspartate residue (Asp189) that is, due to its charged state, well hydrated in the uncomplexed state. We systematically studied the importance of this water molecule by evaluating a series of ligands that contains pyridine-type P1 side chains that could potentially alter the binding properties of this water molecule. All of the pyridine derivatives retain the original hydration state albeit sometimes with a slight perturbance. In order to prevent a direct H-bond formation with Asp189, and to create a permanent positive charge on the P1 side chain that is positioned adjacent to the Asp189 carboxylate anion, we methylated the pyridine nitrogen. This methylation resulted in displacement of water but was accompanied by a loss in binding affinity. Quantum chemical calculations of the ligand solvation free energy showed that the positively charged methylpyridinium derivatives suffer a large penalty of desolvation upon binding. Consequently, they have a substantially less favorable enthalpy of binding. In addition to the ligand desolvation penalty, the hydration shell around Asp189 has to be overcome, which is achieved in nearly all pyridinium derivatives. Only for the ortho derivative is a partial population of a water next to Asp189 found. Possibly, the gain of electrostatic interactions between the charged P1 side chain and Asp189 helps to compensate for the desolvation penalty. In all uncharged pyridine derivatives, the solvation shell remains next to Asp189, partly mediating interactions between ligand and protein. In the case of the para-pyridine derivative, a strongly disordered cluster of water sites is observed between ligand and Asp189.

Articles - 3qtv mentioned but not cited (2)

  1. Automated identification of elemental ions in macromolecular crystal structures. Echols N, Morshed N, Afonine PV, McCoy AJ, Miller MD, Read RJ, Richardson JS, Terwilliger TC, Adams PD. Acta Crystallogr D Biol Crystallogr 70 1104-1114 (2014)
  2. Automating crystallographic structure solution and refinement of protein-ligand complexes. Echols N, Moriarty NW, Klei HE, Afonine PV, Bunkóczi G, Headd JJ, McCoy AJ, Oeffner RD, Read RJ, Terwilliger TC, Adams PD. Acta Crystallogr D Biol Crystallogr 70 144-154 (2014)


Reviews citing this publication (2)

  1. Molecular recognition in chemical and biological systems. Persch E, Dumele O, Diederich F. Angew Chem Int Ed Engl 54 3290-3327 (2015)
  2. Applying thermodynamic profiling in lead finding and optimization. Klebe G. Nat Rev Drug Discov 14 95-110 (2015)

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  1. Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data? Ramírez D, Caballero J. Molecules 23 E1038 (2018)
  2. Homologous ligands accommodated by discrete conformations of a buried cavity. Merski M, Fischer M, Balius TE, Eidam O, Shoichet BK. Proc Natl Acad Sci U S A 112 5039-5044 (2015)
  3. Dynamics Govern Specificity of a Protein-Protein Interface: Substrate Recognition by Thrombin. Fuchs JE, Huber RG, Waldner BJ, Kahler U, von Grafenstein S, Kramer C, Liedl KR. PLoS One 10 e0140713 (2015)
  4. Aromatic Rings Commonly Used in Medicinal Chemistry: Force Fields Comparison and Interactions With Water Toward the Design of New Chemical Entities. Polêto MD, Rusu VH, Grisci BI, Dorn M, Lins RD, Verli H. Front Pharmacol 9 395 (2018)
  5. Identification and In Silico Prediction of Anticoagulant Peptides from the Enzymatic Hydrolysates of Mytilus edulis Proteins. Qiao M, Tu M, Chen H, Mao F, Yu C, Du M. Int J Mol Sci 19 E2100 (2018)
  6. Solvent effects on ligand binding to a serine protease. Gopal SM, Klumpers F, Herrmann C, Schäfer LV. Phys Chem Chem Phys 19 10753-10766 (2017)
  7. Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations. Wahl J, Smieško M. ChemMedChem 13 1325-1335 (2018)
  8. STACKED - Solvation Theory of Aromatic Complexes as Key for Estimating Drug Binding. Loeffler JR, Fernández-Quintero ML, Schauperl M, Liedl KR. J Chem Inf Model 60 2304-2313 (2020)
  9. Polar Desolvation and Position 226 of Pancreatic and Neutrophil Elastases Are Crucial to their Affinity for the Kunitz-Type Inhibitors ShPI-1 and ShPI-1/K13L. Hernández González JE, García-Fernández R, Valiente PA. PLoS One 10 e0137787 (2015)
  10. Conformational Shifts of Stacked Heteroaromatics: Vacuum vs. Water Studied by Machine Learning. Loeffler JR, Fernández-Quintero ML, Waibl F, Quoika PK, Hofer F, Schauperl M, Liedl KR. Front Chem 9 641610 (2021)
  11. Predicting Conserved Water Molecules in Binding Sites of Proteins Using Machine Learning Methods and Combining Features. Xiao W, Ren J, Hao J, Wang H, Li Y, Lin L. Comput Math Methods Med 2022 5104464 (2022)