scholarly journals Concestor kinase activation mechanism uncovers the cyclin dependence of CDK family kinases

2018 ◽  
Author(s):  
Zahra Shamsi ◽  
Diwakar Shukla
Keyword(s):  
Regulatory Elements ◽  
Activation Mechanism ◽  
Energy Landscapes ◽  
Kinase Activation ◽  
Cyclin Dependent Kinases ◽  
Free Energy Landscapes ◽  
Evolutionary Pathways ◽  
Helical Turn ◽  
Dynamics Simulations ◽  
Catalytic Functions

Evolution has altered the free energy landscapes of protein kinases to introduce different regulatory switches and alters their catalytic functions. An understanding of evolutionary pathways behind these changes at atomistic resolution is of great importance for drug design. In this work, we demonstrate how cyclin dependency has emerged in cyclin-dependent kinases (CDKs) by reconstructing their closest experimentally characterized cyclin-independent ancestor. Using available crystal structures of CDK2, regulatory switches are identified and four possible hypotheses describing why CDK2 requires an extra intra-domain regulatory switch compared to the ancestor are formulated. Each hypothesis is tested using all-atom molecular dynamics simulations. Both systems show similar stability in the K33-E51 hydrogen bond and in the alignment of residues in the regulatory-spine, two key protein kinase regulatory elements, while auto-inhibition due to a helical turn in the a-loop is less favorable in the ancestor. The aspartate of the DFG motif does not form a bidentate bond with Mg in CDK2, unlike the ancestor. Using the results of hypothesizes testing, a set of mutations responsible for the changes in CDK2 are identified. Our findings provide a mechanistic rationale for how evolution has added a new regulatory switch to CDK proteins. Moreover, our approach is directly applicable to other proteins.

scholarly journals Free Energy Landscapes and Residue Network Analysis for Six SARS-CoV-2 Targets in Complex with Plausible Phytochemical Inhibitors from Withania Somnifera: 1 µS Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Pratap Kumar Parida ◽  
Dipak Paul ◽  
Debamitra Chakravorty
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Withania Somnifera ◽  
Minimum Energy ◽  
Interaction Network ◽  
Energy Landscapes ◽  
Residue Interaction ◽  
Free Energy Landscapes ◽  
Dynamics Simulations

The pandemic is here to stay- evident from the second wave that is severely affecting global population. Though vaccination is now available, the population size restricts its efficacy, especially in the third world countries. Therefore, to avoid a third wave, natural preventive therapeutics are the need of the hour. In this work the efficiency of phytochemicals from <i>Withania somnifera</i> to bind to a total of six SARS-CoV-2 targets have been shown.1 µs molecular dynamics simulations and essential dynamic analyses shed light on the changes induced by the phytochemicals and highlights their multipotent capabilities- 27-Hydroxywithanolide B was able to bind to three targets. Relative free energy of binding for all the phytochemicals were calculated by MM/PBSA. Minimum energy structures were extracted from their free energy landscapes and were subjected to PSN-ENM-NMA and network centrality analysis. Results showed that the phytochemical binding changes the residue-residue interaction network. Network communities increase while hubs and links decrease. Metapath rewiring occurs through residues Phe456 in spike protein, Thr26 and Tyr118 in main protease, Val49 and Phe156 in NSP3, Leu98 in NSP9, Leu4345 in NSP10, Phe440 and Phe843 in NSP12. This work tries to understand the mechanism of possible inhibition by the phytochemicals to combat SARS-CoV-2 with their capability of targeting multiple proteins. The insight from this study can be of great relevance to explore the changes in network properties induced by reported potential inhibitors against SARS-CoV-2 targets.

scholarly journals Free Energy Landscapes and Residue Network Analysis for Six SARS-CoV-2 Targets in Complex with Plausible Phytochemical Inhibitors from Withania Somnifera: 1 µS Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Pratap Kumar Parida ◽  
Dipak Paul ◽  
Debamitra Chakravorty
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Withania Somnifera ◽  
Minimum Energy ◽  
Interaction Network ◽  
Energy Landscapes ◽  
Residue Interaction ◽  
Free Energy Landscapes ◽  
Dynamics Simulations

The pandemic is here to stay- evident from the second wave that is severely affecting global population. Though vaccination is now available, the population size restricts its efficacy, especially in the third world countries. Therefore, to avoid a third wave, natural preventive therapeutics are the need of the hour. In this work the efficiency of phytochemicals from <i>Withania somnifera</i> to bind to a total of six SARS-CoV-2 targets have been shown.1 µs molecular dynamics simulations and essential dynamic analyses shed light on the changes induced by the phytochemicals and highlights their multipotent capabilities- 27-Hydroxywithanolide B was able to bind to three targets. Relative free energy of binding for all the phytochemicals were calculated by MM/PBSA. Minimum energy structures were extracted from their free energy landscapes and were subjected to PSN-ENM-NMA and network centrality analysis. Results showed that the phytochemical binding changes the residue-residue interaction network. Network communities increase while hubs and links decrease. Metapath rewiring occurs through residues Phe456 in spike protein, Thr26 and Tyr118 in main protease, Val49 and Phe156 in NSP3, Leu98 in NSP9, Leu4345 in NSP10, Phe440 and Phe843 in NSP12. This work tries to understand the mechanism of possible inhibition by the phytochemicals to combat SARS-CoV-2 with their capability of targeting multiple proteins. The insight from this study can be of great relevance to explore the changes in network properties induced by reported potential inhibitors against SARS-CoV-2 targets.

Towards complete descriptions of the free–energy landscapes of proteins

2004 ◽  
Vol 363 (1827) ◽  
pp. 433-452 ◽  
Author(s):  
Michele Vendruscolo ◽  
Christopher M. Dobson
Keyword(s):  
Free Energy ◽  
Resonance Spectroscopy ◽  
Energy Landscapes ◽  
Native Structure ◽  
Wide Range ◽  
Protein Molecules ◽  
Different Types ◽  
Free Energy Landscapes ◽  
Dynamics Simulations ◽  
Do So

In recent years increasingly detailed information about the structures and dynamics of protein molecules has been obtained by innovative applications of experimental techniques, in particular nuclear magnetic resonance spectroscopy and protein engineering, and theoretical methods, notably molecular dynamics simulations. In this article we discuss how such approaches can be combined by incorporating a wide range of different types of experimental data as restraints in computer simulations to provide unprecedented detail about the ensembles of structures that describe proteins in a wide variety of states from the native structure to highly unfolded species. Knowledge of these ensembles is beginning to enable the complete free–energy landscapes of individual proteins to be defined at atomic resolution. This strategy has provided new insights into the mechanism by which proteins are able to fold into their native states, or by which they fail to do so and give rise to harmful aggregates that are associated with a wide range of debilitating human diseases.

FOLDING FREE ENERGY LANDSCAPE OF THE DECAPEPTIDE CHIGNOLIN

2008 ◽  
Vol 22 (31) ◽  
pp. 3087-3098 ◽  
Author(s):  
XIANGHUA DOU ◽  
JIHUA WANG
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Force Fields ◽  
Energy Landscapes ◽  
Native Structure ◽  
Good Template ◽  
Free Energy Landscapes ◽  
Folded Structures ◽  
Dynamics Simulations ◽  
Folding Free Energy

Chignolin is an artificially designed ten-residue (GYDPETGTWG) folded peptide, which is the smallest protein and provides a good template for protein folding. In this work, we completed four explicit water molecular dynamics simulations of Chignolin folding using GROMOS and OPLS-AA force fields from extended initial states without any experiment informations. The four-folding free energy landscapes of the peptide has been drawn. The folded state of Chignolin has been successfully predicated based on the free energy landscapes. The four independent simulations gave similar results. (i) The four free energy landscapes have common characters. They are fairly smooth, barrierless, funnel-like and downhill without intermediate state, which consists with the experiment. (ii) The different extended initial structures converge at similar folded structures with the lowest free energy under GROMOS and OPLS-AA force fields. In the GROMOS force field, the backbone RMSD of the folded structures from the NMR native structure of Chignolin is only 0.114 nm, which is a stable structure in this force field. In the OPLS-AA force field, the similar results have been obtained. In addition, the smallest RMSD structure is in better agreement with the NMR native structure but unlikely stable in the force field.

scholarly journals The complete conformational free energy landscape of β-xylose reveals a two-fold catalytic itinerary for β-xylanases

2015 ◽  
Vol 6 (2) ◽  
pp. 1167-1177 ◽  
Author(s):  
Javier Iglesias-Fernández ◽  
Lluís Raich ◽  
Albert Ardèvol ◽  
Carme Rovira
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio ◽  
Molecular Dynamics Simulations ◽  
Energy Landscape ◽  
Free Energy Landscape ◽  
Energy Landscapes ◽  
Free Energy Landscapes ◽  
Dynamics Simulations ◽  
Conformational Free Energy

Ab initio conformational free energy landscapes, together with molecular dynamics simulations, enable to predict the catalytic itineraries of β-xylanase enzymes.

scholarly journals Molecular Mechanism of Brassinosteroids Perception by the Plant Growth Receptor BRI1

2019 ◽  
Author(s):  
Faisal Aldukhi ◽  
Aniket Deb ◽  
Chuankai Zhao ◽  
Alexander S. Moffett ◽  
Diwakar Shukla
Keyword(s):  
Molecular Mechanism ◽  
Signaling Cascade ◽  
Tyrosine Residue ◽  
Energy Landscapes ◽  
Physiological Processes ◽  
Hydrogen Bonding Interactions ◽  
Free Energy Landscapes ◽  
Dynamics Simulations ◽  
Binding Mechanisms ◽  
Fundamental Mechanism

AbstractBrassinosteroids (BRs) are essential phytohormones which bind to the plant receptor, BRI1, to regulate various physiological processes. The molecular mechanism of the perception of BRs by the ectodomain of BRI1 remains not fully understood. It also remains elusive why a substantial difference in biological activity exists between the BRs. In this work, we study the binding mechanisms of the two most bioactive BRs, brassinolide (BLD) and castasterone (CAT) using molecular dynamics simulations. We report free energy landscapes of the binding processes of both ligands as well as detailed ligand binding pathways. Our results suggest that CAT has lower binding affinity compared to BLD due to its inability to form hydrogen bonding interactions with a tyrosine residue in the island domain of BRI1. We uncover a conserved non-productive binding state for both BLD and CAT, which is more stable for CAT and may further contribute to the bioactivity difference. Finally, we validate past observations about the conformational restructuring and ordering of the island domain upon BLD binding. Overall, this study provides new insights into the fundamental mechanism of the perception of two most bioactive BRs, which may create new avenues for genetic and agrochemical control of their signaling cascade.

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