Flexible fitting of small-molecules into electron microscopy maps using molecular dynamics simulations with Neural Network Potentials.

08:00 EDT 24th March 2020 | BioPortfolio

Summary of "Flexible fitting of small-molecules into electron microscopy maps using molecular dynamics simulations with Neural Network Potentials."

Despite significant advances in resolution, the potential for cryo-electron microscopy (EM) to be used in determining the structures of protein-drug complexes remains unrealized. Determination of accurate structures and coordination of bound ligands necessitates simultaneous fitting of the models into the density envelopes, exhaustive sampling of the ligand geometries, and most importantly, concomitant rearrangements in the sidechains to optimize the binding energy changes. In this article, we present a flexible-fitting pipeline where molecular dynamics flexible fitting (MDFF) is used to refine structures of protein-ligand complexes from 3-5 Å electron density data. Enhanced sampling is employed to explore the binding pockets rearrangements. To provide a model that can accurately describe the conformational dynamics of the chemically-diverse set of small-molecule drugs inside MDFF, we use QM/MM and neural-network potential (NNP)/MM models of protein-ligand complexes, where the ligand is represented using the QM or NNP model and the protein is represented using established molecular mechanical force fields (e.g., CHARMM). This pipeline offers structures commensurate to or better than recently-submitted high-resolution cryo-EM or X-ray models, even when given medium to low-resolution data as input. The use of the NNPs makes the algorithm more robust to the choice of search models, offering a radius of convergence of 6.5 Å for ligand structure determination. The quality of the predicted structures was also judged by density functional theory calculations of ligand strain energy. This strain potential energy is found to systematically decrease with better fitting to density and improved ligand coordination, indicating correct binding interactions. A computationally-inexpensive protocol for computing strain energy is reported as part of the model analysis protocol that monitors both the ligand fit as well as model-quality.


Journal Details

This article was published in the following journal.

Name: Journal of chemical information and modeling
ISSN: 1549-960X


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Medical and Biotech [MESH] Definitions

Microscopy using an electron beam, instead of light, to visualize the sample, thereby allowing much greater magnification. The interactions of ELECTRONS with specimens are used to provide information about the fine structure of that specimen. In TRANSMISSION ELECTRON MICROSCOPY the reactions of the electrons that are transmitted through the specimen are imaged. In SCANNING ELECTRON MICROSCOPY an electron beam falls at a non-normal angle on the specimen and the image is derived from the reactions occurring above the plane of the specimen.

A type of TRANSMISSION ELECTRON MICROSCOPY in which the object is examined directly by an extremely narrow electron beam scanning the specimen point-by-point and using the reactions of the electrons that are transmitted through the specimen to create the image. It should not be confused with SCANNING ELECTRON MICROSCOPY.

Electron microscopy involving rapid freezing of the samples. The imaging of frozen-hydrated molecules and organelles permits the best possible resolution closest to the living state, free of chemical fixatives or stains.

Microscopy in which the object is examined directly by an electron beam scanning the specimen point-by-point. The image is constructed by detecting the products of specimen interactions that are projected above the plane of the sample, such as backscattered electrons. Although SCANNING TRANSMISSION ELECTRON MICROSCOPY also scans the specimen point by point with the electron beam, the image is constructed by detecting the electrons, or their interaction products that are transmitted through the sample plane, so that is a form of TRANSMISSION ELECTRON MICROSCOPY.

Electron microscopy in which the ELECTRONS or their reaction products that pass down through the specimen are imaged below the plane of the specimen.

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