Untitled

Abstract

Many proteins undergo small side chain or even backbone movements on binding of different ligands into the same protein structure. This is known as induced fit and is potentially problematic for virtual screening of databases against protein targets. In this report we investigate the limits of the rigid protein approximation used by the docking program, GOLD, through cross-docking using protein structures of influenza neuraminidase. Neuraminidase is known to exhibit small but significant induced fit effects on ligand binding. Some neuraminidase crystal structures caused concern due to the bound ligand conformation and GOLD performed poorly on these complexes. A 'clean' set, which contained unique, unambiguous complexes, was defined. For this set, the lowest energy structure was correctly docked (i.e. RMSD < 1.5 A away from the crystal reference structure) in 84% of proteins, and the most promiscuous protein (1mwe) was able to dock all 15 ligands accurately including those that normally required an induced fit movement. This is considerably better than the 70% success rate seen with GOLD against general validation sets. Inclusion of specific water molecules involved in water-mediated hydrogen bonds did not significantly improve the docking performance for ligands that formed water-mediated contacts but it did prevent docking of ligands that displaced these waters. Our data supports the use of a single protein structure for virtual screening with GOLD in some applications involving induced fit effects, although care must be taken to identify the protein structure that performs best against a wide variety of ligands. The performance of GOLD was significantly better than the GOLD implementation of ChemScore and the reasons for this are discussed. Overall, GOLD has shown itself to be an extremely good, robust docking program for this system.

PeptiSite: A structural database of peptide binding sites in 4D

“…[18–24] Such conformational changes may range from small-scale side-chain rearrangement to large-scale loop movement or domain shifts. [21, 25–29] Hence, it is significantly difficult to develop an unambiguous structural model of the binding pockets that can be used in computational docking studies. [22, 30–35] The effect of induced fit becomes more crucial for binding sites interacting with peptides due to higher number of conformational degrees of freedom of the ligands.…”

“…Many efforts have been undertaken to account for the structural flexibility in predicting the active conformation of the binding sites[21, 25, 36–54], including building of databases of experimental structures of the protein complexes with small molecule and peptide ligands. [7, 55–61] Comparison of multiple crystal structures of a given protein bound to various ligands can reveal the conformational space that needs to be considered to obtain a correct definition of the binding pocket.…”

Enhancing Virtual Screening Performance of Protein Kinases with Molecular Dynamics Simulations

“…Previous studies have shown similar results - the addition of more conformers can degrade performance. 12, 14–16, 84–86 While ensemble docking studies, ours included, consistently highlight the importance of incorporating multiple protein conformations in VS experiments, that performance does not necessarily scale with ensemble size. Clearly, even though protein kinases may adopt multiple conformations, it appears that only a small number of conformations (1–4) are important for ligand binding, at least in the context of ensemble docking.…”

TSCC: Two-Stage Combinatorial Clustering for virtual screening using protein-ligand interactions and physicochemical features

“…We tested the virtual screening results against the five target proteins: 1) herpes simplex virus type 1 thymidine kinase (TK) [29] PDB identification (ID): lkim, 2) human estrogen receptor alpha (ER α ) [22,30] PDB ID: 3ert, 3) human estrogen receptor alpha (ER α ) PDB ID: lgwr, 4) human dihydrofolate reductase (hDHFR) [31,32] PDB ID: lhfr, and 5) tern n9 influenza virus neuraminidase (NA) [33,34] PDB ID: lmwe.…”