Topics

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.

Affiliation

Journal Details

This article was published in the following journal.

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

Links

DeepDyve research library

PubMed Articles [16095 Associated PubMed Articles listed on BioPortfolio]

Flexible Fitting of Biomolecular Structures to Atomic Force Microscopy Images via Biased Molecular Simulations.

High-speed (HS) atomic force microscopy (AFM) is a prominent imaging technology that observes large-scale structural dynamics of biomolecules near the physiological condition, but the AFM data are lim...

Using cryo-electron microscopy maps for X-ray structure determination of homologues.

The combination of cryo-electron microscopy (cryo-EM) and X-ray crystallography reflects an important trend in structural biology. In a previously published study, a hybrid method for the determinatio...

Protein-Protein Modeling Using Cryo-EM Restraints.

Recent improvements in cryo-electron microscopy (cryo-EM) in the past few years are now allowing to observe molecular complexes at atomic resolution. As a consequence, numerous structures derived from...

Asymmetric density fitting with modified Cholesky decomposition applied to second order electron propagator.

Computation of molecular orbital electron repulsion integrals (MO-ERIs) as a transformation from atomic orbital electron repulsion integrals (AO-ERIs) is the bottleneck of second order electron propag...

Towards large scale orientation mapping using the eCHORD method.

eCHORD is an alternative method for orientation mapping in Scanning Electron Microscopy that involves channeling contrast observed in BSE images. The sample tilt being small (10°), eCHORD could be a ...

Clinical Trials [5293 Associated Clinical Trials listed on BioPortfolio]

Comparison of Characteristics of Bronchoalveolar Lavage Dusting and of Specific Questionnary Data in Healthy Volunteers and Patients Suffering From Sarcoidosis

Comparison of dusting rate of bronchoalveolar lavage in healthy volunteers and patients suffering from sarcoidosis. Blind analysis of bronchoalveolar lavage with Optical Microscopy, Trans...

Internal Limiting Membrane and Macular Hole

Observational study of Internal Limiting Membrane peeled in macular Hole surgery and studied by Transmission electronic Microscopy (TEM) and Optical Coherence Tomography (OCT) findings in ...

Combined Treatment for Tobacco and Alcohol Use in Puerto Rico

Objectives: 1. Assess MAPS and MAPS+ effects on alcohol at-risk behaviors and smoking cessation. 2. Assess MAPS and MAPS+ effects on treatment mechanisms (increased self-efficacy, ...

Evaluation of Patients Who Have Skin Diseases

RATIONALE: Evaluating patients who have skin diseases may help doctors plan more effective treatment and follow-up for skin diseases and systemic diseases that show up in the skin. PURPOS...

Cellular Pharmacodynamics of Small Molecules in Lysosomal Storage Disorders

The purpose of this study is to evaluate the effect of small molecule therapy in primary cells derived from patients with lysosomal storage disease. The study will focus on activity of sma...

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.

Quick Search


DeepDyve research library

Relevant Topics

Pharmacy
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...


Searches Linking to this Article