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Significant enhancement of docking sensitivity using implicit ligand sampling.

ABSTRACT: The efficient and accurate quantification of protein-ligand interactions using computational methods is still a challenging task. Two factors strongly contribute to the failure of docking methods to predict free energies of binding accurately: the insufficient incorporation of protein flexibility coupled to ligand binding and the neglected dynamics of the protein-ligand complex in current scoring schemes. We have developed a new methodology, named the 'ligand-model' concept, to sample protein conformations that are relevant for binding structurally diverse sets of ligands. In the ligand-model concept, molecular-dynamics (MD) simulations are performed with a virtual ligand, represented by a collection of functional groups that binds to the protein and dynamically changes its shape and properties during the simulation. The ligand model essentially represents a large ensemble of different chemical species binding to the same target protein. Representative protein structures were obtained from the MD simulation, and docking was performed into this ensemble of protein conformation. Similar binding poses were clustered, and the averaged score was utilized to rerank the poses. We demonstrate that the ligand-model approach yields significant improvements in predicting native-like binding poses and quantifying binding affinities compared to static docking and ensemble docking simulations into protein structures generated from an apo MD simulation.

SUBMITTER: Xu M

PROVIDER: S-EPMC3172320 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Significant enhancement of docking sensitivity using implicit ligand sampling.

Xu Mengang M Lill Markus A MA

Journal of chemical information and modeling 20110304 3

The efficient and accurate quantification of protein-ligand interactions using computational methods is still a challenging task. Two factors strongly contribute to the failure of docking methods to predict free energies of binding accurately: the insufficient incorporation of protein flexibility coupled to ligand binding and the neglected dynamics of the protein-ligand complex in current scoring schemes. We have developed a new methodology, named the 'ligand-model' concept, to sample protein co ...[more]

PMID: 21375306

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Project description:Protein interactions are key in vital biological processes. In many cases, particularly in regulation, this interaction is between a protein and a shorter peptide fragment. Such peptides are often part of larger disordered regions in other proteins. The flexible nature of peptides enables the rapid yet specific regulation of important functions in cells, such as their life cycle. Consequently, knowledge of the molecular details of peptide-protein interactions is crucial for understanding and altering their function, and many specialized computational methods have been developed to study them. The recent release of AlphaFold and AlphaFold-Multimer has led to a leap in accuracy for the computational modeling of proteins. In this study, the ability of AlphaFold to predict which peptides and proteins interact, as well as its accuracy in modeling the resulting interaction complexes, are benchmarked against established methods. We find that AlphaFold-Multimer predicts the structure of peptide-protein complexes with acceptable or better quality (DockQ ≥0.23) for 66 of the 112 complexes investigated-25 of which were high quality (DockQ ≥0.8). This is a massive improvement on previous methods with 23 or 47 acceptable models and only four or eight high quality models, when using energy-based docking or interaction templates, respectively. In addition, AlphaFold-Multimer can be used to predict whether a peptide and a protein will interact. At 1% false positives, AlphaFold-Multimer found 26% of the possible interactions with a precision of 85%, the best among the methods benchmarked. However, the most interesting result is the possibility of improving AlphaFold by randomly perturbing the neural network weights to force the network to sample more of the conformational space. This increases the number of acceptable models from 66 to 75 and improves the median DockQ from 0.47 to 0.55 (17%) for first ranked models. The best possible DockQ improves from 0.58 to 0.72 (24%), indicating that selecting the best possible model is still a challenge. This scheme of generating more structures with AlphaFold should be generally useful for many applications involving multiple states, flexible regions, and disorder.

Dataset Information

Significant enhancement of docking sensitivity using implicit ligand sampling.

Publications

Significant enhancement of docking sensitivity using implicit ligand sampling.

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