Computational Study of C-X-C Chemokine Receptor (CXCR)3 Binding with Its Natural Agonists Chemokine (C-X-C Motif) Ligand (CXCL)9, 10 and 11 and with Synthetic Antagonists: Insights of Receptor Activation towards Drug Design for Vitiligo

Vitiligo is a hypopigmentary skin pathology resulting from the death of melanocytes due to the activity of CD8+ cytotoxic lymphocytes and overexpression of chemokines. These include CXCL9, CXCL10, and CXCL11 and its receptor CXCR3, both in peripheral cells of the immune system and in the skin of patients diagnosed with vitiligo. The three-dimensional structure of CXCR3 and CXCL9 has not been reported experimentally; thus, homology modeling and molecular dynamics could be useful for the study of this chemotaxis-promoter axis. In this work, a homology model of CXCR3 and CXCL9 and the structure of the CXCR3/Gαi/0βγ complex with post-translational modifications of CXCR3 are reported for the study of the interaction of chemokines with CXCR3 through all-atom (AA-MD) and coarse-grained molecular dynamics (CG-MD) simulations. AA-MD and CG-MD simulations showed the first activation step of the CXCR3 receptor with all chemokines and the second activation step in the CXCR3-CXCL10 complex through a decrease in the distance between the chemokine and the transmembrane region of CXCR3 and the separation of the βγ complex from the α subunit in the G-protein. Additionally, a general protein–ligand interaction model was calculated, based on known antagonists binding to CXCR3. These results contribute to understanding the activation mechanism of CXCR3 and the design of new molecules that inhibit chemokine binding or antagonize the receptor, provoking a decrease of chemotaxis caused by the CXCR3/chemokines axis.

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

Molecules ◽

10.3390/molecules26113293 ◽

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.

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Behavior of Chemokine Receptor 6 (CXCR6) in Complex with CXCL16 Soluble form Chemokine by Molecular Dynamic Simulations: General Protein‒Ligand Interaction Model and 3D-QSAR Studies of Synthetic Antagonists

Life ◽

10.3390/life11040346 ◽

2021 ◽

Vol 11 (4) ◽

pp. 346

Author(s):

Giovanny Aguilera-Durán ◽

Antonio Romo-Mancillas

Keyword(s):

Molecular Dynamics ◽

3D Qsar ◽

Md Simulations ◽

Active State ◽

Activation Mechanism ◽

Soluble Form ◽

Ligand Interaction ◽

Protein Ligand Interaction ◽

Polar Interactions ◽

General Protein

The CXCR6‒CXCL16 axis is involved in several pathological processes, and its overexpression has been detected in different types of cancer, such as prostate, breast, ovary, and lung cancer, along with schwannomas, in which it promotes invasion and metastasis. Moreover, this axis is involved in atherosclerosis, type 1 diabetes, primary immune thrombocytopenia, vitiligo, and other autoimmune diseases, in which it is responsible for the infiltration of different immune system cells. The 3D structure of CXCR6 and CXCL16 has not been experimentally resolved; therefore, homology modeling and molecular dynamics simulations could be useful for the study of this signaling axis. In this work, a homology model of CXCR6 and a soluble form of CXCL16 (CXCR6‒CXCL16s) are reported to study the interactions between CXCR6 and CXCL16s through coarse-grained molecular dynamics (CG-MD) simulations. CG-MD simulations showed the two activation steps of CXCR6 through a decrease in the distance between the chemokine and the transmembrane region (TM) of CXCR6 and transmembrane rotational changes and polar interactions between transmembrane segments. The polar interactions between TM3, TM5, and TM6 are fundamental to functional conformation and the meta-active state of CXCR6. The interactions between D77-R280 and T243-TM7 could be related to the functional conformation of CXCR6; alternatively, the interaction between Q195-Q244 and N248 could be related to an inactive state due to the loss of this interaction, and an arginine cage broken in the presence of CXCL16s allows the meta-active state of CXCR6. A general protein‒ligand interaction supports the relevance of TM3‒TM5‒TM6 interactions, presenting three relevant pharmacophoric features: HAc (H-bond acceptor), HDn (H-bond donator), and Hph (hydrophobic), distributed around the space between extracellular loops (ECLs) and TMs. The HDn feature is close to TM3 and TM6; likewise, the HAc and Hph features are close to ECL1 and ECL2 and could block the rotation and interactions between TM3‒TM6 and the interactions of CXCL16s with the ECLs. Tridimensional quantitative structure-activity relationships (3D-QSAR) models show that the positive steric (VdW) and electrostatic fields coincide with the steric and positive electrostatic region of the exo-azabicyclo[3.3.1]nonane scaffold in the best pIC50 ligands. This substructure is close to the E274 residue and therefore relevant to the activity of CXCR6. These data could help with the design of new molecules that inhibit chemokine binding or antagonize the receptor based on the activation mechanism of CXCR6 and provoke a decrease in chemotaxis caused by the CXCR6‒CXCL16 axis.

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Exploration of inositol 1,4,5-trisphosphate (IP3) regulated dynamics of N-terminal domain of IP3 receptor reveals early phase molecular events during receptor activation

10.1101/404020 ◽

2018 ◽

Author(s):

Aneesh Chandran ◽

Xavier Chee ◽

David L. Prole ◽

Taufiq Rahman

Keyword(s):

Conformational Dynamics ◽

Md Simulations ◽

Receptor Activation ◽

Activation Mechanism ◽

Ip3 Receptor ◽

Dynamic Correlation ◽

Molecular Events ◽

Binding Core ◽

Domain Dynamics ◽

Phosphate Groups

Inositol 1, 4, 5-trisphosphate (IP3) binding at the N-terminus (NT) of IP3 receptor (IP3R) allosterically triggers the opening of a Ca2+-conducting pore located ~ 100 Å away from the IP3-binding core (IBC). However, the precise mechanism of IP3 binding and correlated domain dynamics in the NT that are central to the IP3R activation, remains unknown. Our all-atom molecular dynamics (MD) simulations recapitulate the characteristic twist motion of the suppresser domain (SD) and reveal correlated ‘clam closure’ dynamics of IBC with IP3-binding, complementing existing suggestions on IP3R activation mechanism. Our study further reveals the existence of inter-domain dynamic correlation in the NT and establishes the SD to be critical for the conformational dynamics of IBC. Also, a tripartite interaction involving Glu283-Arg54-Asp444 at the SD – IBC interface seemed critical for IP3R activation. Intriguingly, during the sub-microsecond long simulation, we observed Arg269 undergoing an SD-dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP3. This seems to play a major role in determining the IP3 binding affinity of IBC in the presence/absence of the SD. Our study thus provides atomistic details of early molecular events occurring within the NT during and following IP3 binding that lead to channel gating.

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Antimicrobial action of the cationic peptide, chrysophsin-3: a coarse-grained molecular dynamics study

Soft Matter ◽

10.1039/c7sm02152f ◽

2018 ◽

Vol 14 (15) ◽

pp. 2796-2807 ◽

Cited By ~ 4

Author(s):

Andrea Catte ◽

Mark R. Wilson ◽

Martin Walker ◽

Vasily S. Oganesyan

Keyword(s):

Molecular Dynamics ◽

Large Scale ◽

Md Simulations ◽

Antimicrobial Action ◽

Coarse Grained ◽

Cationic Peptide ◽

Coarse Grained Molecular Dynamics

Antimicrobial action of a cationic peptide is modelled by large scale MD simulations.

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A-Site Distribution in La1−xSrxMnO3: a Computational Study

MRS Proceedings ◽

10.1557/proc-1074-i02-10 ◽

2008 ◽

Vol 1074 ◽

Author(s):

Yun Hee Jang ◽

François Gervais ◽

Yves Lansac

Keyword(s):

Molecular Dynamics ◽

Quantum Mechanics ◽

Colossal Magnetoresistance ◽

Computational Study ◽

Mixed Valence ◽

Magnetic Tunnel Junction ◽

Md Simulations ◽

Site Distribution ◽

Mixed Valence Manganites ◽

A Site

ABSTRACTThe possibility of an A-site (La3+/Sr2+) ordering in a colossal magnetoresistance manganite (CMR) La3/4Sr1/4MnO3 was explored using molecular dynamics (MD) simulations with a newly developed force field (FF) and quantum mechanics (QM) calculations on the structures obtained from MD. The calculated degrees of stabilization (enthalpy gain) of various patterns of A-site ordering are not significant enough to overcome the accompanying entropy loss, supporting the random A-site distribution in La3/4Sr1/4MnO3. This approach combining MD and QM as well as the versatile FF developed in this study should be useful to investigate the structures and functions of magnetic tunnel junction devices involving mixed-valence manganites.

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Simulating Absorption Spectra of Flavonoids in Aqueous Solution: A Polarizable QM/MM Study

Molecules ◽

10.3390/molecules25245853 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5853

Author(s):

Sulejman Skoko ◽

Matteo Ambrosetti ◽

Tommaso Giovannini ◽

Chiara Cappelli

Keyword(s):

Molecular Dynamics ◽

Aqueous Solution ◽

Hydrogen Bonding ◽

Force Field ◽

Absorption Spectra ◽

Computational Study ◽

Md Simulations ◽

Quantum Mechanical ◽

Hydrogen Bonding Interactions

We present a detailed computational study of the UV/Vis spectra of four relevant flavonoids in aqueous solution, namely luteolin, kaempferol, quercetin, and myricetin. The absorption spectra are simulated by exploiting a fully polarizable quantum mechanical (QM)/molecular mechanics (MM) model, based on the fluctuating charge (FQ) force field. Such a model is coupled with configurational sampling obtained by performing classical molecular dynamics (MD) simulations. The calculated QM/FQ spectra are compared with the experiments. We show that an accurate reproduction of the UV/Vis spectra of the selected flavonoids can be obtained by appropriately taking into account the role of configurational sampling, polarization, and hydrogen bonding interactions.

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Solvent-induced depletion interactions in multiparticle collision dynamic simulations

International Journal of Modern Physics C ◽

10.1142/s0129183119410080 ◽

2019 ◽

Vol 30 (10) ◽

pp. 1941008 ◽

Cited By ~ 2

Author(s):

Martin Wagner ◽

Marisol Ripoll

Keyword(s):

Molecular Dynamics ◽

Md Simulations ◽

Coarse Grained ◽

Simulation Methods ◽

Mesoscale Simulation ◽

Dynamic Simulations ◽

Collision Dynamic ◽

Versatile Tool ◽

Depletion Interactions

Molecular-dynamics-coupled multiparticle collision dynamic (MPC-MD) simulations have emerged to be an efficient and versatile tool in the description of mesoscale colloidal dynamics. However, the compressibility of the coarse-grained fluid leads to this method being prone to spurious depletion interactions that may dominate the colloidal dynamics. In this paper, we review the existing methodology to deal with these interactions, establish and report depletion measurements, and present a method to avoid artificial depletion in mesoscale simulation methods.

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Molecular Dynamics Simulations of Diffusion of O2 and N2 Penetrants in Polydimethylsiloxane-Based Nanocomposites

Journal of Engineering Materials and Technology ◽

10.1115/1.4005921 ◽

2012 ◽

Vol 134 (2) ◽

Cited By ~ 10

Author(s):

Douglas E. Spearot ◽

Alex Sudibjo ◽

Varun Ullal ◽

Adam Huang

Keyword(s):

Molecular Dynamics ◽

Polymer Composites ◽

Diffusion Coefficients ◽

Metal Particle ◽

Interatomic Potential ◽

Md Simulations ◽

Coarse Grained ◽

Cu Nanoparticles ◽

Cu Nanoparticle ◽

Nanoparticle Inclusions

Recently, metal particle polymer composites have been proposed as sensing materials for micro corrosion sensors. To design the sensors, a detailed understanding of diffusion through metal particle polymer composites is necessary. Accordingly, in this work molecular dynamics (MD) simulations are used to study the diffusion of O2 and N2 penetrants in metal particle polymer nanocomposites composed of an uncross-linked polydimethylsiloxane (PDMS) matrix with Cu nanoparticle inclusions. PDMS is modeled using a hybrid interatomic potential with explicit treatment of Si and O atoms along the chain backbone and coarse-grained methyl side groups. In most models examined in this work, MD simulations show that diffusion coefficients of O2 and N2 molecules in PDMS-based nanocomposites are lower than that in pure PDMS. Nanoparticle inclusions act primarily as geometric obstacles for the diffusion of atmospheric penetrants, reducing the available porosity necessary for diffusion, with instances of O2 and N2 molecule trapping also observed at or near the PDMS/Cu nanoparticle interfaces. In models with the smallest gap between Cu nanoparticles, MD simulations show that O2 and N2 diffusion coefficients are higher than that in pure PDMS at the lowest temperatures studied. This is due to PDMS chain confinement at low temperatures in the presence of the Cu nanoparticles, which induces low-density regions within the PDMS matrix. MD simulations show that the role of temperature on diffusion can be modeled using the Williams–Landel–Ferry equation, with parameters influenced by nanoparticle content and spacing.

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Effective interaction between small unilamellar vesicles as probed by coarse-grained molecular dynamics simulations

Pure and Applied Chemistry ◽

10.1515/pac-2014-5023 ◽

2014 ◽

Vol 86 (2) ◽

pp. 215-222 ◽

Cited By ~ 8

Author(s):

Wataru Shinoda ◽

Michael L. Klein

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Effective Interaction ◽

Md Simulations ◽

Coarse Grained ◽

Repulsive Interaction ◽

Spontaneous Curvature ◽

Unilamellar Vesicles ◽

Small Unilamellar Vesicles ◽

Dynamics Simulations

Abstract A series of molecular dynamics (MD) simulations has been undertaken to investigate the effective interaction between vesicles including PC (phosphatidylcholine) and PE (phosphatidylethanolamine) lipids using the Shinoda–DeVane–Klein coarse-grained force field. No signatures of fusion were detected during MD simulations employing two apposed unilamellar vesicles, each composed of 1512 lipid molecules. Association free energy of the two stable vesicles depends on the lipid composition. The two PC vesicles exhibit a purely repulsive interaction with each other, whereas two PE vesicles show a free energy gain at the contact. A mixed PC/PE (1:1) vesicle shows a higher flexibility having a lower energy barrier on the deformation, which is caused by lipid sorting within each leaflet of the membranes. With a preformed channel or stalk between proximal membranes, PE molecules contribute to stabilize the stalk. The results suggest that the lipid components forming the membrane with a negative spontaneous curvature contribute to stabilize the stalk between two vesicles in contact.

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OR24-01 Mutational Study of the GPR119 Receptor Binding Site

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1659 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Matthew D Rosales ◽

Frank Dean ◽

Evangelia Kotsikorou

Keyword(s):

Hydrogen Bonding ◽

Binding Site ◽

Specific Activity ◽

Md Simulations ◽

Binding Pocket ◽

Receptor Activation ◽

Activation Mechanism ◽

Receptor Model ◽

Wild Type

Abstract The GPR119 receptor, a class A G-protein coupled receptor located in the pancreatic β cells, induces insulin production when activated. Due to its specific activity, the pharmaceutical industry has identified GPR119 as a target for the treatment for type 2 diabetes. The lack of a GRP119 crystal structure has hindered the study of the receptor so our laboratory developed GPR119 active and inactive homology models. Docking studies with the inactive receptor model indicated that two leucine residues facing the binding pocket, L5.43(169) and L6.52(242), may be involved in ligand activation. Additionally, a serine at the extracellular end of the pocket, S1.32(4), may help orient of the ligand in the binding pocket via hydrogen bonding. To gain further insight into the role of these residues and the receptor activation mechanism, molecular dynamics (MD) simulations and in vitro cAMP assays of the wild type and mutant receptors were employed. The software NAMD employing the CHARMM force field was used to carry out MD simulations of the active receptor model bound with the agonist AR231453 embedded in a hydrated lipid bilayer. Preliminary results indicate that L6.52(242), located on transmembrane helix (TMH) 6, does not face directly into the binding site and does not interact with the ligand, while L5.43(169), located on TMH5, does face into the binding site, potentially interacting directly with the ligand. Also, S1.32(4), because of its extracellular location, is solvated instead of interacting with the ligand. The in vitro studies overall support the MD simulations. The mutations L6.52(242)M and L6.52(242)A appear to have minimal to no effect on agonist-induced cAMP production, compared to the wild type. In contrast, the L5.43(169)M and L5.43(169)A mutations decrease the potency of activation by AR231453, indicating that L5.43(169) changes the shape of the binding pocket, affecting ligand binding and activation. Finally, the cAMP assays show that the S1.32(4)A mutant also shows decreased activity compared to the wild type, implying that the ligand may be losing a hydrogen bonding interaction when S1.32(4) is mutated to alanine.

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