Testing a Flexible-receptor Docking Algorithm in a Model Binding Site

Wei, BinQing; Weaver, L.H.; Ferrari, Anna Maria; Matthews, Brian W.; Shoichet, Brian K.

doi:10.1016/j.jmb.2004.02.015

Cited by 184 publications

(210 citation statements)

References 58 publications

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“…However, docking to alternate protein conformations seems not to result in significant improvements in the quality of docking results, except when many different crystallographic protein conformations are used. 31 A large source of error in docking is the rigid-protein approximation Docking typically treats proteins as rigid. How big is the error introduced by this assumption?…”

Section: Alchemical Methods Are More Accurate Than Dockingmentioning

confidence: 99%

“…[20][21][22][23][24][25]58 Here, to isolate sources of error, we study a highly simplified binding site using alchemical free energy methods and molecular dynamics. We focus on the binding of small aromatic ligands to the small, buried hydrophobic binding site in an engineered mutant of T4 lysozyme (the L99A site; Figure 1) that has been studied extensively experimentally, [26][27][28][29][30][31][32] with docking methods, 30,32 and in some previous computational free energy studies. 18,19,23,33 Here we systematically evaluate the effect of various approximations on computed binding free energies.…”

Section: Introductionmentioning

confidence: 99%

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Predicting Absolute Ligand Binding Free Energies to a Simple Model Site

Mobley

Graves

Chodera

et al. 2007

Journal of Molecular Biology

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311

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A central challenge in structure-based ligand design is the accurate prediction of binding free energies. Here we apply alchemical free energy calculations in explicit solvent to predict ligand binding in a model cavity in T4 lysozyme. Even in this simple site, there are challenges. We made systematic improvements, beginning with single poses from docking, then including multiple poses, additional protein conformational changes, and using an improved charge model. Computed absolute binding free energies had an RMS error of 1.9 kcal/mol relative to previously determined experimental values. In blind prospective tests, the methods correctly discriminated between several true ligands and decoys in a set of putative binders identified by docking. In these prospective tests, the RMS error in predicted binding free energies relative to those subsequently determined experimentally was only 0.6 kcal/mol. X-ray crystal structures of the new ligands bound in the cavity corresponded closely to predictions from the free energy calculations, but sometimes differed from those predicted by docking. Finally, we examined the impact of holding the protein rigid, as in docking, with a view to learning how approximations made in docking affect accuracy and how they may be improved.

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Section: Alchemical Methods Are More Accurate Than Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predicting Absolute Ligand Binding Free Energies to a Simple Model Site

Mobley

Graves

Chodera

et al. 2007

Journal of Molecular Biology

Self Cite

311

501

View full text Add to dashboard Cite

show abstract

“…57 This was shown for protein-ligand interactions, 58 protein-protein docking 59,60 and even protein design. 10,28,29,[61][62][63] But it is very difficult to access such ensembles by experimental methods.…”

Section: Introductionmentioning

confidence: 96%

Backbone Flexibility Controls the Activity and Specificity of a Protein−Protein Interface: Specificity in Snake Venom Metalloproteases

et al. 2010

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Protein-protein interfaces have crucial functions in many biological processes. The large interaction areas of such interfaces show complex interaction motifs. Even more challenging is the understanding of (multi)specificity in protein-protein binding. Many proteins can bind several partners to mediate their function. A perfect paradigm to study such multispecific protein-protein interfaces are snake venom metalloproteases (SVMPs). Inherently, they bind to a variety of basement membrane proteins of capillaries, hydrolyze them, and induce profuse bleeding. However, despite having a high sequence homology, some SVMPs show a strong hemorrhagic activity, while others are (almost) inactive. We present computer simulations indicating that the activity to induce hemorrhage, and thus the capability to bind the potential reaction partners, is related to the backbone flexibility in a certain surface region. A subtle interplay between flexibility and rigidity of two loops seems to be the prerequisite for the proteins to carry out their damaging function. Presumably, a significant alteration in the backbone dynamics makes the difference between SVMPs that induce hemorrhage and the inactive ones.

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“…The binding of the protein to the ligand is analogous to the fitting of the key to the lock due to the complementary structure between the ligand and the active site of the protein. The other theory is the 'induced fit' where the proteins and the ligands make adjustment in their conformation to result in the best electronic fit [50]. Thus the optimized conformation between ligand and the targets (here proteins) results in the orientations between them, showing minimum energy.…”

Section: Molecular Recognitionmentioning

confidence: 99%

Natural compounds for the drug targets of Sexually Transmitted Diseases (STD) using virtual screening

2013

IOSR-JPBS

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Testing a Flexible-receptor Docking Algorithm in a Model Binding Site

Cited by 184 publications

References 58 publications

Predicting Absolute Ligand Binding Free Energies to a Simple Model Site

Predicting Absolute Ligand Binding Free Energies to a Simple Model Site

Backbone Flexibility Controls the Activity and Specificity of a Protein−Protein Interface: Specificity in Snake Venom Metalloproteases

Natural compounds for the drug targets of Sexually Transmitted Diseases (STD) using virtual screening

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