Characterizing the interaction modes of PAR4 receptor with agonist and antagonist by molecular simulation approach

2019 ◽  
Vol 18 (02) ◽  
pp. 1950008
Author(s):  
Nan Lu ◽  
Fancui Meng ◽  
Jing Yuan ◽  
Lei Liu ◽  
Yanshi Wang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Structural Characteristics ◽  
Principal Component ◽  
Activation Mechanism ◽  
Binding Modes ◽  
Dynamic Simulations ◽  
Extracellular Region ◽  
Agonist And Antagonist

Protease-activated receptor 4 (PAR4) is a promising target for antiplatelet therapy. In this study, homology modeling and molecular docking methods were used to investigate the binding modes of PAR4 agonists and antagonists. The outcomes show that agonists have good docking scores, and they also form more hydrogen bonds with PAR4 than antagonists. To reveal the different conformational changes caused by agonist and antagonist, molecular dynamic simulations were carried out on three selected PAR4 systems. Simulation results show that PAR4 activation involves breaking interactions of 3–7 lock switch (Try157 and Tyr322) and ionic lock switch (Arg188 and Asp173), and formation of transmission switch among Tyr161, Asn300 and Phe296. In addition, principal component analysis (PCA) indicates that the major change for agonist bound system takes place in the intracellular region while that for antagonist bound system is in the extracellular region. The binding free energy of BMS-986120 is much lower than AYPGKF, suggesting high affinity of antagonist. Moreover, the electronegative aspartic residues Asp230 and Asp235 at ECL2 are important for PAR4 binding to agonist. Clarifying the PAR4 structural characteristics may be helpful to understand the activation mechanism, giving insights into the molecular design and discovery of novel potential PAR4 antagonists in the future.

scholarly journals Deciphering PD1 activation mechanism from molecular docking and molecular dynamic simulations

2021 ◽  
Author(s):  
Luis F. Ponce ◽  
Daniel P. Ramirez-Echemendia ◽  
Kalet Leon ◽  
Pedro A. Valiente
Keyword(s):  
T Cells ◽  
Molecular Docking ◽  
Cellular Membrane ◽  
Umbrella Sampling ◽  
Activation Mechanism ◽  
Binding Modes ◽  
Dynamic Simulations ◽  
Linear Lattice ◽  
High Molecular Weight Complex ◽  
Inhibitory Mechanisms

AbstractThe activation of T cells is normally accompanied by inhibitory mechanisms within which the PD1 receptor stands out. Upon binding the ligands PDL1 and PDL2, PD1 drives T cells to an unresponsive state called exhaustion characterized by a markedly decreased capacity to exert effector functions. For this reason, PD1 has become one of the most important targets in cancer immunotherapy. Despite the numerous studies about PD1 signaling modulation, how the PD1 signaling is activated upon the ligands’ binding remains an open question. Several experimental facts suggest that the activation of the PD1-PLD1 pathway depends on the interaction with an unknown partner at the cellular membrane. In this work, we investigate the possibility that the target of PD1-PDL1 is the same PD1-PDL1 complex. We combined molecular docking to explore different binding modes with molecular dynamics and umbrella sampling simulations to assess the complexes’ stability. We found a high molecular weight complex that explains the activation of PD1 upon PDL1 binding. This complex has an affinity comparable to the PD1-PDL1 interaction and resembles the form of a linear lattice.

scholarly journals Structural Insights into Sphingosine-1-phosphate Receptor Activation

2022 ◽  
Author(s):  
Leiye Yu ◽  
Licong He ◽  
Bing Gan ◽  
Rujuan Ti ◽  
Qingjie Xiao ◽  
...  
Keyword(s):  
Transition Process ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Structural Basis ◽  
Lymphoid Tissues ◽  
Binding Modes ◽  
Dynamic Simulations ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Key Steps

As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1-5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or non-lipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its non-redundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here we reported four atomic resolution cryo-EM structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod ((S)-FTY720-P), or non-lipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step "shallow to deep" transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1P receptors.

TMEM16A protein: calcium binding site and its activation mechanism

2021 ◽  
Vol 28 ◽  
Author(s):  
Wanying Ji ◽  
Donghong Shi ◽  
Sai Shi ◽  
Xiao Yang ◽  
Yafei Chen ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Calcium Ions ◽  
Calcium Binding ◽  
Molecular Design ◽  
Chloride Ion ◽  
Activation Mechanism ◽  
Calcium Binding Site ◽  
Key Issues ◽  
Function Relationship ◽  
And Function

: TMEM16A mediates calcium-activated transmembrane flow of chloride ion and a variety of physiological functions. The binding of cytoplasmic calcium ions of TMEM16A and the consequent conformational changes of it are the key issues to explore the relationship between its structure and function. In recent years, researchers have explored this issue through electrophysiological experiment, structure resolving, molecular dynamic simulation and other methods. The structures of TMEM16 family members resolved by cryo-Electron microscopy (cryo-EM) and X-ray crystallization provide the primarily basis for the investigation of the molecular mechanism of TMEM16A. However, the binding and activation mechanism of calcium ions in TMEM16A are still unclear and controversial. This review discusses four Ca2+ sensing sites of TMEM16A and analyze activation properties of TMEM16A by them, which will help to understand the structure-function relationship of TMEM16A and throw light on the molecular design targeting TMEM16A channel.

scholarly journals Repositioning of fungal-based peptides as modulators of angiotensin-converting enzyme-related carboxypeptidase, SARS-coronavirus HR2 domain, and coronavirus disease 2019 main protease

2021 ◽  
Vol 9 (3) ◽  
pp. 190-199
Author(s):  
Babatunde Joseph Oso ◽  
Clement Olusola Ogidi
Keyword(s):  
Free Energy ◽  
Angiotensin Converting Enzyme ◽  
Binding Free Energy ◽  
Binding Modes ◽  
Converting Enzyme ◽  
Sars Coronavirus ◽  
Dynamic Simulations ◽  
Medicinal Mushrooms ◽  
Main Protease ◽  
Cellular Entry

Abstract Background and Objectives Angiotensin-converting enzyme-related carboxypeptidase, SARS-Coronavirus HR2 Domain, and COVID-19 main protease are essential for the cellular entry and replication of coronavirus in the host. This study investigated the putative inhibitory action of peptides form medicinal mushrooms, namely Pseudoplectania nigrella, Russula paludosa, and Clitocybe sinopica, towards selected proteins through computational studies. Materials and Methods The respective physicochemical properties of selected peptides were predicted using ProtParam tool, while the binding modes and binding free energy of selected peptides toward proteins were computed through HawkDock server. The structural flexibility and stability of docked protein–peptide complexes were assessed through iMODS server. Results The peptides showed an optimum binding afinity with the molecular targets; plectasin from P. nigrella showed the highest binding free energy compared to peptides from R. paludosa and C. sinopica. Besides, molecular dynamic simulations showed all fungal-based peptides could influence the flexibility and stability of selected proteins. Conclusion The study revealed fungal-based peptides could be explored as functional modulators of essential proteins that are involved in the cellular entry of coronavirus.

Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Mechanisms ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

scholarly journals Impact of Deuteration and Temperature on Furan Ring Dynamics

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2889
Author(s):  
Przemyslaw Dopieralski ◽  
Iryna V. Omelchenko ◽  
Zdzislaw Latajka
Keyword(s):  
Conformational Changes ◽  
Furan Ring ◽  
Computational Studies ◽  
Significant Progress ◽  
Dynamic Simulations ◽  
Cyclic Molecules ◽  
Ring Dynamics ◽  
Different Temperatures ◽  
Long Time ◽  
Shape And Size

Despite significant progress in conformational analysis of cyclic molecules, the number of computational studies is still limited while most of that available in the literature data have been obtained long time ago with outdated methods. In present research, we have studied temperature driven conformational changes of the furan ring at three different temperatures. Additionally, the effect of deuteration on the ring dynamics is discussed; in addition, the aromaticity indices following the Bird and HOMA schemes are computed along all trajectories. Our ab initio molecular dynamic simulations revealed that deuteration has changed the furan ring dynamics and the obvious consequences; in addition, the shape and size of molecule are expected to be different.

scholarly journals The Odd Faces of Oligomers: The Case of TRAF2-C, A Trimeric C-Terminal Domain of TNF Receptor-Associated Factor

2021 ◽  
Vol 22 (11) ◽  
pp. 5871
Author(s):  
Almerinda Di Venere ◽  
Eleonora Nicolai ◽  
Velia Minicozzi ◽  
Anna Maria Caccuri ◽  
Luisa Di Paola ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Strong Dependence ◽  
Conformational Dynamics ◽  
Receptor Interaction ◽  
Tnf Receptor ◽  
Oligomeric State ◽  
Dynamic Simulations ◽  
Associated Factor ◽  
Terminal Domain

TNF Receptor Associated Factor 2 (TRAF2) is a trimeric protein that belongs to the TNF receptor associated factor family (TRAFs). The TRAF2 oligomeric state is crucial for receptor binding and for its interaction with other proteins involved in the TNFR signaling. The monomer-trimer equilibrium of a C- terminal domain truncated form of TRAF2 (TRAF2-C), plays also a relevant role in binding the membrane, causing inward vesiculation. In this study, we have investigated the conformational dynamics of TRAF2-C through circular dichroism, fluorescence, and dynamic light scattering, performing temperature-dependent measurements. The data indicate that the protein retains its oligomeric state and most of its secondary structure, while displaying a significative increase in the heterogeneity of the tyrosines signal, increasing the temperature from ≈15 to ≈35 °C. The peculiar crowding of tyrosine residues (12 out of 18) at the three subunit interfaces and the strong dependence on the trimer concentration indicate that such conformational changes mainly involve the contact areas between each pair of monomers, affecting the oligomeric state. Molecular dynamic simulations in this temperature range suggest that the interfaces heterogeneity is an intrinsic property of the trimer that arises from the continuous, asymmetric approaching and distancing of its subunits. Such dynamics affect the results of molecular docking on the external protein surface using receptor peptides, indicating that the TRAF2-receptor interaction in the solution might not involve three subunits at the same time, as suggested by the static analysis obtainable from the crystal structure. These findings shed new light on the role that the TRAF2 oligomeric state might have in regulating the protein binding activity in vivo.

scholarly journals Approximating deformation fields for the analysis of continuous heterogeneity of biological macromolecules by 3D Zernike polynomials

IUCrJ ◽  
2021 ◽  
Vol 8 (6) ◽  
Author(s):  
David Herreros ◽  
Roy R. Lederman ◽  
James Krieger ◽  
Amaya Jiménez-Moreno ◽  
Marta Martínez ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Structural Characteristics ◽  
Normal Mode Analysis ◽  
Principal Component ◽  
Current Data ◽  
Mode Analysis ◽  
Biological Macromolecules ◽  
Mathematical Basis ◽  
Common Framework ◽  
Low Dimensional

Structural biology has evolved greatly due to the advances introduced in fields like electron microscopy. This image-capturing technique, combined with improved algorithms and current data processing software, allows the recovery of different conformational states of a macromolecule, opening new possibilities for the study of its flexibility and dynamic events. However, the ensemble analysis of these different conformations, and in particular their placement into a common variable space in which the differences and similarities can be easily recognized, is not an easy matter. To simplify the analysis of continuous heterogeneity data, this work proposes a new automatic algorithm that relies on a mathematical basis defined over the sphere to estimate the deformation fields describing conformational transitions among different structures. Thanks to the approximation of these deformation fields, it is possible to describe the forces acting on the molecules due to the presence of different motions. It is also possible to represent and compare several structures in a low-dimensional mapping, which summarizes the structural characteristics of different states. All these analyses are integrated into a common framework, providing the user with the ability to combine them seamlessly. In addition, this new approach is a significant step forward compared with principal component analysis and normal mode analysis of cryo-electron microscopy maps, avoiding the need to select components or modes and producing localized analysis.

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