scholarly journals Protocols for all-atom reconstruction and high-resolution refinement of protein-peptide complex structures

2019 ◽  
Author(s):  
Aleksandra Badaczewska-Dawid ◽  
Alisa Khramushin ◽  
Andrzej Kolinski ◽  
Ora Schueler-Furman ◽  
Sebastian Kmiecik
Keyword(s):  
Molecular Docking ◽  
High Resolution ◽  
Protein Complexes ◽  
Structural Models ◽  
Structure Optimization ◽  
Complex Structures ◽  
Peptide Models ◽  
Peptide Complexes ◽  
High Resolution Models ◽  
Structural Characterizations

SummaryStructural characterizations of protein-peptide complexes may require further improvements. These may include reconstruction of missing atoms and/or structure optimization leading to higher accuracy models. In this work, we describe a workflow that generates accurate structural models of peptide-protein complexes starting from protein-peptide models in C-alpha representation generated using CABS-dock molecular docking. First, protein-peptide models are reconstructed from their C-alpha traces to all-atom representation using MODELLER. Next, they are refined using RosettaFlexPepDock. The described workflow allows for reliable all-atom reconstruction of CABS-dock models and their further improvement to high-resolution models.

scholarly journals Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

2020 ◽  
Author(s):  
Aleksandra E Badaczewska-Dawid ◽  
Sebastian Kmiecik ◽  
Michał Koliński
Keyword(s):  
High Resolution ◽  
Molecular Mechanisms ◽  
Cyclic Peptide ◽  
Peptide Ligands ◽  
New Drugs ◽  
Structural Description ◽  
Deviation Measure ◽  
Peptide Complexes ◽  
High Resolution Models ◽  
G Protein Coupled

Abstract The structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein–peptide complex structures and model scoring. We evaluated the proposed protocol on the set of seven different GPCR–peptide complexes (including one containing a cyclic peptide), for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface root-mean-square-deviation measure.

scholarly journals Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

2020 ◽  
Author(s):  
Aleksandra E. Badaczewska-Dawid ◽  
Sebastian Kmiecik ◽  
Michał Koliński
Keyword(s):  
High Resolution ◽  
Molecular Mechanisms ◽  
Cyclic Peptide ◽  
Peptide Ligands ◽  
New Drugs ◽  
Structural Description ◽  
Peptide Complexes ◽  
Crystallographic Structures ◽  
High Resolution Models ◽  
G Protein Coupled

AbstractThe structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein-peptide complex structures and model scoring. We evaluated the proposed protocol on the set of 7 different GPCR-peptide complexes (including one containing a cyclic peptide) for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface RMSD measure.

Exploring the Active Compounds of Traditional Mongolian Medicine Agsirga in Intervention of Novel Coronavirus (2019-nCoV) Based on HPLC-Q-Exactive-MS/MS and Molecular Docking Method

2020 ◽  
Author(s):  
Jie Cheng ◽  
Yuchen Tang ◽  
Baoquan Bao ◽  
Ping Zhang
Keyword(s):  
Mass Spectrometry ◽  
Molecular Docking ◽  
High Resolution ◽  
Mass Spectra ◽  
High Resolution Mass Spectrometry ◽  
Structural Formula ◽  
Active Compounds ◽  
High Resolution Mass ◽  
Q Exactive ◽  
Resolution Mass

<p><a></a><a></a><a></a><a><b>Objective</b></a>: To screen all compounds of Agsirga based on the HPLC-Q-Exactive high-resolution mass spectrometry and find potential inhibitors that can respond to 2019-nCoV from active compounds of Agsirga by molecular docking technology.</p> <p><b>Methods</b>: HPLC-Q-Exactive high-resolution mass spectrometry was adopted to identify the complex components of Mongolian medicine Agsirga, and separated by the high-resolution mass spectrometry Q-Exactive detector. Then the Orbitrap detector was used in tandem high-resolution mass spectrometry, and the related molecular and structural formula were found by using the chemsipider database and related literature, combined with precise molecular formulas (errors ≤ 5 × 10<sup>−6</sup>) , retention time, primary mass spectra, and secondary mass spectra information, The fragmentation regularities of mass spectra of these compounds were deduced. Taking ACE2 as the receptor and deduced compounds as the ligand, all of them were pretreated by discover studio, autodock and Chem3D. The molecular docking between the active ingredients and the target protein was studied by using AutoDock molecular docking software. The interaction between ligand and receptor is applied to provide a choice for screening anti-2019-nCoV drugs.</p> <p><b>Result</b>: Based on the fragmentation patterns of the reference compounds and consulting literature, a total of 96 major alkaloids and stilbenes were screened and identified in Agsirga by the HPLC-Q-Exactive-MS/MS method. Combining with molecular docking, a conclusion was got that there are potential active substances in Mongolian medicine Agsirga which can block the binding of ACE2 and 2019-nCoV at the molecular level.</p>

Three-dimensional crystallization of membrane proteins

1988 ◽  
Vol 21 (4) ◽  
pp. 429-477 ◽  
Author(s):  
W. Kühlbrandt
Keyword(s):  
High Resolution ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Protein Complexes ◽  
Three Dimensional ◽  
Biological Macromolecules ◽  
X Ray ◽  
X Ray Crystallography ◽  
Membrane Protein Complexes ◽  
Essential Prerequisite

As recently as 10 years ago, the prospect of solving the structure of any membrane protein by X-ray crystallography seemed remote. Since then, the threedimensional (3-D) structures of two membrane protein complexes, the bacterial photosynthetic reaction centres of Rhodopseudomonas viridis (Deisenhofer et al. 1984, 1985) and of Rhodobacter sphaeroides (Allen et al. 1986, 1987 a, 6; Chang et al. 1986) have been determined at high resolution. This astonishing progress would not have been possible without the pioneering work of Michel and Garavito who first succeeded in growing 3-D crystals of the membrane proteins bacteriorhodopsin (Michel & Oesterhelt, 1980) and matrix porin (Garavito & Rosenbusch, 1980). X-ray crystallography is still the only routine method for determining the 3-D structures of biological macromolecules at high resolution and well-ordered 3-D crystals of sufficient size are the essential prerequisite.

scholarly journals Molecular Dynamics Scoring of Protein–Peptide Models Derived from Coarse-Grained Docking

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3293
Author(s):  
Mateusz Zalewski ◽  
Sebastian Kmiecik ◽  
Michał Koliński
Keyword(s):  
Molecular Dynamics ◽  
Geometry Optimization ◽  
Computational Prediction ◽  
Md Simulations ◽  
Coarse Grained ◽  
Ligand Interaction ◽  
Vast Number ◽  
Docking Simulations ◽  
Peptide Models ◽  
Peptide Complexes

One of the major challenges in the computational prediction of protein–peptide complexes is the scoring of predicted models. Usually, it is very difficult to find the most accurate solutions out of the vast number of sometimes very different and potentially plausible predictions. In this work, we tested the protocol for Molecular Dynamics (MD)-based scoring of protein–peptide complex models obtained from coarse-grained (CG) docking simulations. In the first step of the scoring procedure, all models generated by CABS-dock were reconstructed starting from their original C-alpha trace representations to all-atom (AA) structures. The second step included geometry optimization of the reconstructed complexes followed by model scoring based on receptor–ligand interaction energy estimated from short MD simulations in explicit water. We used two well-known AA MD force fields, CHARMM and AMBER, and a CG MARTINI force field. Scoring results for 66 different protein–peptide complexes show that the proposed MD-based scoring approach can be used to identify protein–peptide models of high accuracy. The results also indicate that the scoring accuracy may be significantly affected by the quality of the reconstructed protein receptor structures.

scholarly journals Size and spatial correlation of defective domains in yttrium-doped CeO2

2015 ◽  
Vol 30 (S1) ◽  
pp. S119-S126 ◽  
Author(s):  
Stefano Checchia ◽  
Marco Scavini ◽  
Mattia Allieta ◽  
Michela Brunelli ◽  
Claudio Ferrero ◽  
...  
Keyword(s):  
Distribution Function ◽  
High Resolution ◽  
Pair Distribution Function ◽  
Structural Models ◽  
Resolution Function ◽  
Reliable Model ◽  
Close Relationship ◽  
Instrumental Resolution ◽  
Doped Ceo2 ◽  
Low Symmetry

The size of dopant-rich nanodomains was assessed in four samples of Ce1−μYμO2−μ/2 through systematic pair distribution function (PDF) refinements. Experimental G(r) curves were fitted by different structural models with the aim of finding a description which balanced precise structure parameterization and reasonable number of parameters. The most reliable model was a single Y2O3-like phase, which best accommodated to the close relationship between the fluorite (CeO2-like) and C-type (Y2O3-like) structures. In this model, a refined cation coordinate, x(M2), measured the relative occurrence in the G(r) of the chemical environment of Y and Ce at any value of r. The r-value at which x(M2) vanished, i.e. at which the refined C-type cell becomes a redundant, low-symmetry description of a fluorite cell, was assumed as the size of a C-type domain. Subtle features in G(r) could be attributed to the fluorite or C-type phase up to ~500 Å thanks to the narrow instrumental resolution function of the ID31 beamline (now ID22) at the ESRF, which allows us to get high resolution PDF data.

scholarly journals Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

2017 ◽  
Vol 2017 ◽  
pp. 1-25 ◽  
Author(s):  
Viviana I. Torres ◽  
Daniela Vallejo ◽  
Nibaldo C. Inestrosa
Keyword(s):  
Central Nervous System ◽  
Neurological Disorders ◽  
Neuronal Development ◽  
Protein Complexes ◽  
Synaptic Proteins ◽  
Excitatory Synapses ◽  
Complex Structures ◽  
Disease Phenotype ◽  
The Central Nervous System ◽  
Invertebrate Models

Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype.

Confocal fluorescence microscopy with the tandem scanning light microscope

1989 ◽  
Vol 94 (4) ◽  
pp. 617-624
Author(s):  
S.J. Wright ◽  
J.S. Walker ◽  
H. Schatten ◽  
C. Simerly ◽  
J.J. McCarthy ◽  
...  
Keyword(s):  
High Resolution ◽  
Fluorescence Microscopy ◽  
Light Microscope ◽  
Three Dimensional ◽  
Three Dimensions ◽  
Complex Structures ◽  
Charge Coupled Device ◽  
Confocal Fluorescence ◽  
Cooled Ccd ◽  
Cellular Components

Applications of the tandem scanning confocal microscope (TSM) to fluorescence microscopy and its ability to resolve fluorescent biological structures are described. The TSM, in conjunction with a cooled charge-coupled device (cooled CCD) and conventional epifluorescence light source and filter sets, provided high-resolution, confocal data, so that different fluorescent cellular components were distinguished in three dimensions within the same cell. One of the unique features of the TSM is the ability to image fluorochromes excited by ultraviolet light (e.g. Hoechst, DAPI) in addition to fluorescein and rhodamine. Since the illumination is dim, photobleaching is insignificant and prolonged viewing of living specimens is possible. Series of optical sections taken in the Z-axis with the TSM were reproduced as stereo images and three-dimensional reconstructions. These data show that the TSM is potentially a powerful tool in fluorescence microscopy for determining three-dimensional relationships of complex structures within cells labeled with multiple fluorochromes.

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