scholarly journals Binding of Ca2+-Independent C2 Domains to Lipid Membranes: a Multi-Scale Molecular Dynamics Study

2020 ◽  
Author(s):  
Andreas Haahr Larsen ◽  
Mark S.P. Sansom
Keyword(s):  
Molecular Dynamics ◽  
Lipid Bilayers ◽  
Md Simulations ◽  
Multiscale Simulation ◽  
Coarse Grained ◽  
Type I ◽  
Type Ii ◽  
Binding Modes ◽  
C2 Domains ◽  
Anionic Lipids

AbstractC2 domains facilitate protein-lipid interaction in cellular recognition and signalling processes. They possess a β-sandwich structure, with either type I or type II topology. C2 domains can interact with anionic lipid bilayers in either a Ca2+-dependent or a Ca2+-independent manner. The mechanism of recognition of anionic lipids by Ca2+-independent C2 domains is incompletely understood. We have used molecular dynamics (MD) simulations to explore the membrane interactions of six Ca2+– independent C2 domains, from KIBRA, PI3KC2α, RIM2, PTEN, SHIP2, and Smurf2. In coarse grained MD simulations these C2 domains bound to lipid bilayers, forming transient interactions with zwitterionic (phosphatidylcholine, PC) bilayers compared to long lived interactions with anionic bilayers also containing either phosphatidylserine (PS) or PS and phosphatidylinositol bisphosphate (PIP2). Type I C2 domains bound non-canonically via the front, back or side of the β sandwich, whereas type II C2 domains bound canonically, via the top loops (as is typically the case for Ca2+-dependent C2 domains). C2 domains interacted strongly (up to 120 kJ/mol) with membranes containing PIP2 causing the bound anionic lipids to clustered around the protein. The C2 domains bound less strongly to anionic membranes without PIP2 (<50 kJ/mol), and most weakly to neutral membranes (<33 kJ/mol). Productive binding modes were identified and further analysed in atomistic simulations. For PTEN and SHIP2, CG simulations were also performed of the intact enzymes (i.e. phosphatase domain plus C2 domain) with PIP2-contating bilayers and the roles of the two domains in membrane localization were compared. From a methodological perspective, these studies establish a multiscale simulation protocol for studying membrane binding/recognition proteins, capable of revealing binding modes alongside details of lipid binding affinity and specificity.

Interactions of peripheral proteins with model membranes as viewed by molecular dynamics simulations

2014 ◽  
Vol 42 (5) ◽  
pp. 1418-1424 ◽  
Author(s):  
Antreas C. Kalli ◽  
Mark S. P. Sansom
Keyword(s):  
Lipid Bilayers ◽  
Molecular Mechanisms ◽  
Phospholipid Composition ◽  
Md Simulations ◽  
Multiscale Simulation ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Peripheral Proteins ◽  
Dynamics Simulations ◽  
Phosphatidylinositol Phosphates

Many cellular signalling and related events are triggered by the association of peripheral proteins with anionic lipids in the cell membrane (e.g. phosphatidylinositol phosphates or PIPs). This association frequently occurs via lipid-binding modules, e.g. pleckstrin homology (PH), C2 and four-point-one, ezrin, radixin, moesin (FERM) domains, present in peripheral and cytosolic proteins. Multiscale simulation approaches that combine coarse-grained and atomistic MD simulations may now be applied with confidence to investigate the molecular mechanisms of the association of peripheral proteins with model bilayers. Comparisons with experimental data indicate that such simulations can predict specific peripheral protein–lipid interactions. We discuss the application of multiscale MD simulation and related approaches to investigate the association of peripheral proteins which contain PH, C2 or FERM-binding modules with lipid bilayers of differing phospholipid composition, including bilayers containing multiple PIP molecules.

scholarly journals A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery

2017 ◽  
Author(s):  
Wei Chen ◽  
Zhiye Tang ◽  
Tim Cholko ◽  
Chia-en A. Chang
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Ligand Binding ◽  
Md Simulations ◽  
Electrostatic Energy ◽  
Major Protein ◽  
Type I ◽  
Type Ii ◽  
Protein Motions ◽  
The Stability

AbstractThe activities of CDK8 with partner Cyclin C (CycC) are a common feature of many diseases, especially cancers. Here we report the study of dynamic behaviors and energy profiles of 13 CDK8/CycC systems, including the DMG-in and DMG-out conformations as well as 5 type I ligands and 5 type II ligands, with all-atom unbiased molecular dynamics (MD) simulations. We observed numerous regional motions within CDK8, which move in concert to form five major protein motions. The motion of the activation loop doesn’t appear to influence the binding of both types of ligands. Type I ligands remarkably reduce the motion of the C-terminal tail through the strong cation-π interaction between the ligands and ARG356, and type II ligands stabilize the αC helix by forming stable hydrogen bonds with GLU66. The MD calculations also confirmed the importance of CycC to the stability of the CDK8 system as well as the ligand binding. The MMPB/SA results show that van der Waals interaction is the main driving force for the binding of both types of ligands, but electrostatic energy and entropy penalty plays important roles in the binding of type II ligands. The volume analysis results indicate that the induced fitting theory applies in the binding of type I ligands. These results would help to improve the affinities of the existing ligands. Our MD work is complementary to crystal structures and may have implications in the development of new CDK8 inhibitors as well as in the field of drug discovery.

Molecular-dynamics studies on solid phase epitaxy of guest-free silicon clathrates

2001 ◽  
Vol 691 ◽  
Author(s):  
Shinji Munetoh ◽  
Koji Moriguchi ◽  
Teruaki Motooka ◽  
Kazuhito Kamei
Keyword(s):  
Activation Energy ◽  
Molecular Dynamics ◽  
Structural Transition ◽  
Solid Phase ◽  
Experimental Studies ◽  
Md Simulations ◽  
Type I ◽  
Solid Phase Epitaxy ◽  
Type Ii ◽  
Silicon Clathrates

ABSTRACTDynamical phenomena during the solid phase epitaxy (SPE) of guest-free Si clathrates (Si34 and Si46) via molecular-dynamics (MD) simulations using the Tersoff potential have been reported. The activation energy of SPE for Si34 has been found to correspond with the experimental value for the cubic diamond phase (c-Si; approximately 2.7eV), while the SPE rates of Si46 are much lower than that of c-Si. The structural transition from Si46 (type-I) to Si34 (type-II) can be also observed during the Si46 [001] SPE. The present results suggest that it is worthwhile to intensify experimental studies concerning crystal growth techniques of clathrate materials and these interesting Si forms may open up a new field in “silicon technologies”.

Concurrent Coupling of Electronic-Density-Functional, Molecular Dynamics, and Coarse-Grained Particles Schemes for Multiscale Simulation of Nanostructured Materials

2005 ◽  
Vol 502 ◽  
pp. 33-38 ◽  
Author(s):  
Shuji Ogata ◽  
Takahiro Igarashi
Keyword(s):  
Molecular Dynamics ◽  
Nanostructured Materials ◽  
Density Functional ◽  
Dft Method ◽  
Md Simulations ◽  
Multiscale Simulation ◽  
Coarse Grained ◽  
Dynamic Simulations ◽  
Electronic Density ◽  
Wide Range

Feature sizes of useful electronic devices are becoming smaller and reaching nanometer ranges. There is increasing demand to perform dynamic simulations of such nano-devices with realistic sizes. To date, various kinds of simulation methods have been used for materials and devices including the density-functional theory (DFT) and the molecular dynamics (MD) for atomistic mechanics and the finite element method for continuum mechanics. We review recent progresses in our multiscale, hybrid simulation schemes that combine those methods. The coarse-grained particles (CG) method originally proposed by Rudd and Broughton [Phys. Rev. B58 (1998), p. R5893] has features suitable to such hybridization. We improve the CG method so that it is applicable to realistic nanostructured materials with large deformations. A novel hybridization scheme that couples the DFT method with the MD method is presented, which is applicable to virtually any selection of the DFT region in a wide range of materials. Hybrid DFT-MD simulations of the H2O reaction with nanostructured Si and alumina systems under stresses are performed, to demonstrate significant effects of stress on the chemical reaction.

scholarly journals Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christopher Agnew ◽  
Pelin Ayaz ◽  
Risa Kashima ◽  
Hanna S. Loving ◽  
Prajakta Ghatpande ◽  
...  
Keyword(s):  
Md Simulations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Type I ◽  
Type Ii ◽  
Exchange Mass Spectrometry ◽  
Receptor Complexes ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Smad Proteins

AbstractUpon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

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

Soft Matter ◽  
2018 ◽  
Vol 14 (15) ◽  
pp. 2796-2807 ◽  
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.

scholarly journals 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

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4413
Author(s):  
Giovanny Aguilera-Durán ◽  
Antonio Romo-Mancillas
Keyword(s):  
Molecular Dynamics ◽  
Computational Study ◽  
Md Simulations ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Coarse Grained ◽  
Dimensional Structure ◽  
Cytotoxic Lymphocytes ◽  
Ligand Interaction ◽  
Α Subunit

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.

scholarly journals In Silico Study of the Mechanism of Binding of the N-Terminal Region of α Synuclein to Synaptic-Like Membranes

Life ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 98 ◽  
Author(s):  
Carlos Navarro-Paya ◽  
Maximo Sanz-Hernandez ◽  
Alfonso De Simone
Keyword(s):  
Lipid Bilayers ◽  
Conformational Transition ◽  
Md Simulations ◽  
Bound State ◽  
Terminal Region ◽  
Coarse Grained ◽  
Biological Behavior ◽  
In Silico Study ◽  
Membrane Bound ◽  
Presynaptic Protein

The membrane binding by α-synuclein (αS), a presynaptic protein whose aggregation is strongly linked with Parkinson’s disease, influences its biological behavior under functional and pathological conditions. This interaction requires a conformational transition from a disordered-unbound to a partially helical membrane-bound state of the protein. In the present study, we used enhanced coarse-grained MD simulations to characterize the sequence and conformational determinants of the binding to synaptic-like vesicles by the N-terminal region of αS. This region is the membrane anchor and is of crucial importance for the properties of the physiological monomeric state of αS as well as for its aberrant aggregates. These results identify the key factors that play a role in the binding of αS with synaptic lipid bilayers in both membrane-tethered and membrane-locked conformational states.

Raf promotes dimerization of the Ras G-domain with increased allosteric connections

2020 ◽  
Author(s):  
Morgan Packer ◽  
Jillian A. Parker ◽  
Jean K. Chung ◽  
Zhenlu Li ◽  
Young Kwang Lee ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Lipid Bilayers ◽  
Md Simulations ◽  
Size Exclusion ◽  
Supported Lipid Bilayers ◽  
Erk Pathway ◽  
Signaling Complex ◽  
Macromolecular Assembly ◽  
High Affinity ◽  
Exclusion Chromatography

AbstractRas dimerization is critical for Raf activation, yet Ras alone does not dimerize. Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics (MD) simulations show robust allosteric connections linking the two Raf-RBD D113 residues, located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 Å apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway.

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