scholarly journals Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Maciej Pawel Ciemny ◽  
Aleksander Debinski ◽  
Marta Paczkowska ◽  
Andrzej Kolinski ◽  
Mateusz Kurcinski ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Conformational Changes ◽  
Large Scale

scholarly journals An extensive survey of molecular docking tools and their applications using text mining and deep curation strategies.

2019 ◽  
Author(s):  
Kamal Rawal ◽  
Tanishka Khurana ◽  
Himanshu Sharma ◽  
Sadika Verma ◽  
Simmi Gupta ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Text Mining ◽  
Conformational Changes ◽  
Large Scale ◽  
Drug Repositioning ◽  
Experimental Studies ◽  
Time Frame ◽  
Literature Mining ◽  
Scoring Functions ◽  
Basic Features

The technology of docking molecules in-silico has evolved significantly in recent years and has become a crucial component of the drug discovery tool process that includes virtual screening, lead optimization, and side-effect predictions. To date over 43,000 abstracts/papers have been published on docking, thereby highlighting the importance of this computational approach in the context of drug development. Considering the large amount of genomic and proteomic consortia active in the public domain, docking can exploit this data on a correspondingly ‘large scale’ to address a variety of research questions. Over 160 robust and accurate molecular docking tools based on different algorithms have been made available to users across the world. Further, 109 scoring functions have been reported in the literature till date. Despite these advancements, there continue to be several bottlenecks during the implementation stage. These problems or issues range from choosing the right docking algorithm, selecting a binding site in target proteins, performance of the given docking tool, integration of molecular dynamics information, ligand-induced conformational changes, use of solvent molecules, choice of docking pose, and choice of databases. Further, so far, not always have experimental studies been used to validate the docking results. In this review, basic features and key concepts of docking have been highlighted, with particular emphasis on its applications such as drug repositioning and prediction of side effects. Also, the use of docking in conjunction with wet lab experimentations and epitope predictions has been summarized. Attempts have been made to systematically address the above-mentioned challenges using expert-curation and text mining strategies. Our work shows the use of machine-assisted literature mining to process and analyze huge amounts of available information in a short time frame. With this work, we also propose to build a platform that combines human expertise (deep curation) and machine learning in a collaborative way and thus helps to solve ambitious problems (i.e. building fast, efficient docking systems by combining the best tools or to perform large scale docking at human proteome level).

scholarly journals An extensive survey of molecular docking tools and their applications using text mining and deep curation strategies.

2019 ◽  
Author(s):  
Kamal Rawal ◽  
Tanishka Khurana ◽  
Himanshu Sharma ◽  
Sadika Verma ◽  
Simmi Gupta ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Text Mining ◽  
Conformational Changes ◽  
Large Scale ◽  
Drug Repositioning ◽  
Experimental Studies ◽  
Time Frame ◽  
Literature Mining ◽  
Scoring Functions ◽  
Basic Features

The technology of docking molecules in-silico has evolved significantly in recent years and has become a crucial component of the drug discovery tool process that includes virtual screening, lead optimization, and side-effect predictions. To date over 43,000 abstracts/papers have been published on docking, thereby highlighting the importance of this computational approach in the context of drug development. Considering the large amount of genomic and proteomic consortia active in the public domain, docking can exploit this data on a correspondingly ‘large scale’ to address a variety of research questions. Over 160 robust and accurate molecular docking tools based on different algorithms have been made available to users across the world. Further, 109 scoring functions have been reported in the literature till date. Despite these advancements, there continue to be several bottlenecks during the implementation stage. These problems or issues range from choosing the right docking algorithm, selecting a binding site in target proteins, performance of the given docking tool, integration of molecular dynamics information, ligand-induced conformational changes, use of solvent molecules, choice of docking pose, and choice of databases. Further, so far, not always have experimental studies been used to validate the docking results. In this review, basic features and key concepts of docking have been highlighted, with particular emphasis on its applications such as drug repositioning and prediction of side effects. Also, the use of docking in conjunction with wet lab experimentations and epitope predictions has been summarized. Attempts have been made to systematically address the above-mentioned challenges using expert-curation and text mining strategies. Our work shows the use of machine-assisted literature mining to process and analyze huge amounts of available information in a short time frame. With this work, we also propose to build a platform that combines human expertise (deep curation) and machine learning in a collaborative way and thus helps to solve ambitious problems (i.e. building fast, efficient docking systems by combining the best tools or to perform large scale docking at human proteome level).

scholarly journals Metastable Intermediates as Stepping Stones on the Maturation Pathways of Viral Capsids

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Giovanni Cardone ◽  
Robert L. Duda ◽  
Naiqian Cheng ◽  
Lili You ◽  
James F. Conway ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Large Scale ◽  
Structural Changes ◽  
Energy Landscape ◽  
Potential Hazard ◽  
Stepping Stones ◽  
Scanning Calorimetry ◽  
Conformational Effects ◽  
Capsid Maturation ◽  
Capsid Integrity

ABSTRACT As they mature, many capsids undergo massive conformational changes that transform their stability, reactivity, and capacity for DNA. In some cases, maturation proceeds via one or more intermediate states. These structures represent local minima in a rich energy landscape that combines contributions from subunit folding, association of subunits into capsomers, and intercapsomer interactions. We have used scanning calorimetry and cryo-electron microscopy to explore the range of capsid conformations accessible to bacteriophage HK97. To separate conformational effects from those associated with covalent cross-linking (a stabilization mechanism of HK97), a cross-link-incompetent mutant was used. The mature capsid Head I undergoes an endothermic phase transition at 60°C in which it shrinks by 7%, primarily through changes in its hexamer conformation. The transition is reversible, with a half-life of ~3 min; however, >50% of reverted capsids are severely distorted or ruptured. This observation implies that such damage is a potential hazard of large-scale structural changes such as those involved in maturation. Assuming that the risk is lower for smaller changes, this suggests a rationalization for the existence of metastable intermediates: that they serve as stepping stones that preserve capsid integrity as it switches between the radically different conformations of its precursor and mature states. IMPORTANCE Large-scale conformational changes are widespread in virus maturation and infection processes. These changes are accompanied by the release of conformational free energy as the virion (or fusogenic glycoprotein) switches from a precursor state to its mature state. Each state corresponds to a local minimum in an energy landscape. The conformational changes in capsid maturation are so radical that the question arises of how maturing capsids avoid being torn apart. Offering proof of principle, severe damage is inflicted when a bacteriophage HK97 capsid reverts from the (nonphysiological) state that it enters when heated past 60°C. We suggest that capsid proteins have been selected in part by the criterion of being able to avoid sustaining collateral damage as they mature. One way of achieving this—as with the HK97 capsid—involves breaking the overall transition down into several smaller steps in which the risk of damage is reduced.

scholarly journals Exploiting the Reverse Vaccinology Approach to Design Novel Subunit Vaccine against Ebola Virus

2020 ◽  
Author(s):  
Md. Asad Ullah ◽  
Bishajit Sarkar ◽  
Syed Sajidul Islam
Keyword(s):  
Molecular Docking ◽  
Mhc Class Ii ◽  
Large Scale ◽  
Matrix Protein ◽  
Ebola Virus ◽  
Rna Virus ◽  
Docking Study ◽  
Dynamics Simulation ◽  
Molecular Docking Study ◽  
Class I Mhc

AbstractEbola virus is a highly pathogenic RNA virus that causes haemorrhagic fever in human. With very high mortality rate, Ebola virus is considered as one of the dangerous viruses in the world. Although, the Ebola outbreaks claimed many lives in the past, no satisfactory treatment or vaccine have been discovered yet to fight against Ebola. For this reason, in this study, various tools of bioinformatics and immunoinformatics were used to design possible vaccines against Zaire Ebola virus strain Mayinga-76. To construct the vaccine, three potential antigenic proteins of the virus, matrix protein VP40, envelope glycoprotein and nucleoprotein were selected against which the vaccines would be designed. The MHC class-I, MHC class-II and B-cell epitopes were determined and after robust analysis through various tools and molecular docking analysis, three vaccine candidates, designated as EV-1, EV-2 and EV-3, were constructed. Since the highly conserved epitopes were used for vaccine construction, these vaccine constructs are also expected to be effective on other strains of Ebola virus like strain Gabon-94 and Kikwit-95. Next, the molecular docking study on these vaccine constructs were analyzed by molecular docking study and EV-1 emerged as the best vaccine construct. Later, molecular dynamics simulation study revealed the good performances as well as good stability of the vaccine protein. Finally, codon adaptation and in silico cloning were conducted to design a possible plasmid (pET-19b plasmid vector was used) for large scale, industrial production of the EV-1 vaccine.

scholarly journals Nuclear pores constrict upon energy depletion

2020 ◽  
Author(s):  
Christian E Zimmerli ◽  
Matteo Allegretti ◽  
Vasileios Rantos ◽  
Sara K Goetz ◽  
Agnieszka Obarska-Kosinska ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Large Scale ◽  
Electron Tomography ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Energy Status ◽  
Energy Depletion ◽  
Time Variations ◽  
Subtomogram Averaging ◽  
Pore Complexes

Nuclear pore complexes (NPCs) fuse the inner and outer nuclear membranes and mediate nucleocytoplasmic exchange. They are made of 30 different nucleoporins that form an intricate cylindrical architecture around an aqueous central channel. This architecture is highly dynamic in space and time. Variations in NPC diameter were reported, but the physiological circumstances and the molecular details remain unknown. Here we combined cryo-electron tomography and subtomogram averaging with integrative structural modeling to capture a molecular movie of the respective large-scale conformational changes in cellulo. While actively transporting NPCs adopt a dilated conformation, they strongly constrict upon cellular energy depletion. Fluorescence recovery after photo bleaching experiments show that NPC constriction is concomitant with reduced diffusion and active transport across the nuclear envelope. Our data point to a model where the energy status of cells is linked to the conformation of NPC architecture.

scholarly journals Structural insights into the activation of human calcium-sensing receptor

2021 ◽  
Author(s):  
Xiaochen Chen ◽  
Lu Wang ◽  
Zhanyu Ding ◽  
Qianqian Cui ◽  
Li Han ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Large Scale ◽  
Transmembrane Domains ◽  
Structural Basis ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Cryo Electron Microscopy ◽  
Activation Mechanisms ◽  
G Protein Coupled ◽  
Structural Insights

AbstractHuman calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and active states. Complemented with previously reported crystal structures of CaSR extracellular domains, it suggests that there are three distinct conformations: inactive, intermediate and active state during the activation. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca2+ ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data shows that the agonist binding leads to the compaction of the dimer, the proximity of the cysteine-rich domains, the large-scale transitions of 7-transmembrane domains, and the inter-and intrasubunit conformational changes of 7-transmembrane domains to accommodate the downstream transducers. Our results reveal the structural basis for activation mechanisms of the CaSR.

scholarly journals Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 848
Author(s):  
Ger T. Rijkers ◽  
Nynke Weterings ◽  
Andres Obregon-Henao ◽  
Michaëla Lepolder ◽  
Taru S. Dutt ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Conformational Changes ◽  
Dna Sequences ◽  
Neutralizing Antibodies ◽  
Large Scale ◽  
Viral Vector ◽  
Adenovirus Vector ◽  
Platelet Factor ◽  
Immune Mediated ◽  
Protein Encoding

Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of viral Spike S1 protein encoding mRNA incorporated in a lipid nanoparticle and stabilized by polyethylene glycol (PEG). The mRNA vaccines are novel in many respects, including cellular uptake and the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences, encoding the SARS-CoV-2 Spike protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to the induction of virus-neutralizing antibodies and cytotoxic T-lymphocytes, will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. The mRNA-based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG and potential presentation in the context of CD1 will be discussed. Adenovirus vector-based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.

scholarly journals Simplified geometric representations of protein structures identify complementary interaction interfaces

2019 ◽  
Author(s):  
Caitlyn L. McCafferty ◽  
Edward M. Marcotte ◽  
David W. Taylor
Keyword(s):  
Conformational Changes ◽  
Protein Interaction ◽  
Protein Function ◽  
Large Scale ◽  
Predictive Accuracy ◽  
Protein Complexes ◽  
Protein Structures ◽  
Molecular Properties ◽  
3D Structures ◽  
Geometric Representations

ABSTRACTProtein-protein interactions are critical to protein function, but three-dimensional (3D) arrangements of interacting proteins have proven hard to predict, even given the identities and 3D structures of the interacting partners. Specifically, identifying the relevant pairwise interaction surfaces remains difficult, often relying on shape complementarity with molecular docking while accounting for molecular motions to optimize rigid 3D translations and rotations. However, such approaches can be computationally expensive, and faster, less accurate approximations may prove useful for large-scale prediction and assembly of 3D structures of multi-protein complexes. We asked if a reduced representation of protein geometry retains enough information about molecular properties to predict pairwise protein interaction interfaces that are tolerant of limited structural rearrangements. Here, we describe a cuboid transformation of 3D protein accessible surfaces on which molecular properties such as charge, hydrophobicity, and mutation rate can be easily mapped, implemented in the MorphProt package. Pairs of surfaces are compared to rapidly assess partner-specific potential surface complementarity. On two available benchmarks of 85 overall known protein complexes, we observed F1 scores (a weighted combination of precision and recall) of 19-34% at correctly identifying protein interaction surfaces, comparable to more computationally intensive 3D docking methods in the annual Critical Assessment of PRedicted Interactions. Furthermore, we examined the effect of molecular motion through normal mode simulation on a benchmark receptor-ligand pair and observed no marked loss of predictive accuracy for distortions of up to 6 Å RMSD. Thus, a cuboid transformation of protein surfaces retains considerable information about surface complementarity, offers enhanced speed of comparison relative to more complex geometric representations, and exhibits tolerance to conformational changes.

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