Multiscale simulation of small peptides: Consistent conformational sampling in atomistic and coarse-grained models

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.

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

10.1101/2020.10.30.361964 ◽

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.

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An overview of data-driven HADDOCK strategies in CAPRI rounds 38-45

10.1101/718122 ◽

2019 ◽

Author(s):

P.I. Koukos ◽

J. Roel-Touris ◽

F. Ambrosetti ◽

C. Geng ◽

J. Schaarschmidt ◽

...

Keyword(s):

Scoring Function ◽

Data Driven ◽

Coarse Grained ◽

Conformational Sampling ◽

Model Quality ◽

Sustained Performance ◽

Docking Approach ◽

Binding Pockets ◽

Integrate Data ◽

Modelling Process

ABSTRACTOur information-driven docking approach HADDOCK has demonstrated a sustained performance since the start of its participation to CAPRI. This is due, in part, to its ability to integrate data into the modelling process, and to the robustness of its scoring function. We participated in CAPRI both as server and as manual predictors.In CAPRI rounds 38-45, we have used various strategies depending on the information at hand. These ranged from imposing restraints to a few residues identified from literature as being important for the interaction, to binding pockets identified from homologous complexes or template-based refinement / CA-CA restraint-guided docking from identified templates. When relevant, symmetry restraints were used to limit the conformational sampling. We also tested for a large decamer target a new implementation of the MARTINI coarse-grained force field in HADDOCK. Overall in the current rounds, we obtained acceptable or better predictions for 13 and 11 server and manual submissions, respectively, out of the 22 interfaces. Our server performance (acceptable models) was better (59%) than the manual (50%) one, in which we typically experiment with various combinations of protocols and data sources. Again, our simple scoring function based on a linear combination of intermolecular van der Waals and electrostatic energies and an empirical desolvation term demonstrated a good performance in the scoring experiment with a 63% success rate across all 22 interfaces.An analysis of model quality indicates that, while we are consistently performing well in generating acceptable models, there is room for improvement for generating/identifying higher quality models.

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Transport Mechanisms Underlying Ionic Conductivity in Nanoparticle-Based Single-Ion Electrolytes

10.26434/chemrxiv.12510545.v2 ◽

2020 ◽

Author(s):

Sanket Kadulkar ◽

Delia Milliron ◽

Thomas Truskett ◽

Venkat Ganesan

Keyword(s):

Ionic Conductivities ◽

Solvent Polarity ◽

Multiscale Simulation ◽

Coarse Grained ◽

Design Parameters ◽

Transport Pathways ◽

Surface Transport ◽

High Particle ◽

Conductivity Increase ◽

Ion Conducting

<div>Recent studies have demonstrated the potential of nanoparticle-based single-ion conductors as battery electrolytes. In this work, we introduce a coarse-grained multiscale simulation approach to identify the mechanisms underlying the ion mobilities in such systems and to clarify the influence of key design parameters on conductivity. Our results suggest that for the experimentally studied electrolyte systems, the dominant pathway for cation transport is along the surface of nanoparticles, in the vicinity of nanoparticle-tethered anions. At low nanoparticle concentrations, connectivity of cationic surface transport pathways and conductivity increase with nanoparticle loading. However, cation mobilities are reduced when nanoparticles are in close vicinity, causing conductivity to decrease for suffciently high particle loadings. We discuss the impacts of cation and anion choice as well as solvent polarity within this picture and suggest means to enhance ionic conductivities in single-ion conducting electrolytes based on nanoparticle salts.</div>

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Transport Mechanisms Underlying Ionic Conductivity in Nanoparticle-Based Single-Ion Electrolytes

10.26434/chemrxiv.12510545 ◽

2020 ◽

Author(s):

Sanket Kadulkar ◽

Delia Milliron ◽

Thomas Truskett ◽

Venkat Ganesan

Keyword(s):

Ionic Conductivities ◽

Solvent Polarity ◽

Multiscale Simulation ◽

Coarse Grained ◽

Design Parameters ◽

Transport Pathways ◽

Surface Transport ◽

High Particle ◽

Conductivity Increase ◽

Ion Conducting

<div>Recent studies have demonstrated the potential of nanoparticle-based single-ion conductors as battery electrolytes. In this work, we introduce a coarse-grained multiscale simulation approach to identify the mechanisms underlying the ion mobilities in such systems and to clarify the influence of key design parameters on conductivity. Our results suggest that for the experimentally studied electrolyte systems, the dominant pathway for cation transport is along the surface of nanoparticles, in the vicinity of nanoparticle-tethered anions. At low nanoparticle concentrations, connectivity of cationic surface transport pathways and conductivity increase with nanoparticle loading. However, cation mobilities are reduced when nanoparticles are in close vicinity, causing conductivity to decrease for suffciently high particle loadings. We discuss the impacts of cation and anion choice as well as solvent polarity within this picture and suggest means to enhance ionic conductivities in single-ion conducting electrolytes based on nanoparticle salts.</div>

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Self-assembly of small peptide amphiphiles, the structures formed and their applications. (A foods and home and personal care perspective)

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2015.0138 ◽

2016 ◽

Vol 374 (2072) ◽

pp. 20150138 ◽

Cited By ~ 11

Author(s):

W. J. Frith

Keyword(s):

Recent Work ◽

Computer Simulations ◽

Self Assembly ◽

Coarse Grained ◽

Gel Formation ◽

Small Peptides ◽

Huge Number ◽

Small Peptide ◽

Microscopic Scale ◽

Future Developments

In this opinion piece, some specific challenges in the field of peptide self-assembly and gel formation are discussed. One major hurdle to finding functional small peptides is that there are a huge number of compounds to explore, which increases exponentially with the peptide size. This in itself creates a barrier to the discovery and application of materials, both through the difficulty of finding the peptides, and because protecting inventions also becomes more difficult. Recent work has shown that computer simulations may provide us a route to explore such a huge compound space; this is discussed along with the prospect for future developments. At the microscopic scale, many fibril-forming peptides form gels, apparently through a process of lateral association of primary self-assembled filaments, which leads to a relatively coarse-grained structure of rigid interconnects. However, recent data obtained on Fmoc-tyrosine gels appear to indicate that the gel microstructure is both more flexible and finer grained than previously believed. As such, it is clear that there is a considerable amount that is still not understood regarding this class of gel. This article is part of the themed issue ‘Soft interfacial materials: from fundamentals to formulation’.

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114 Multiscale simulation of crack propagation with hybrid atomistic/coarse-grained-particle method

The Proceedings of The Computational Mechanics Conference ◽

10.1299/jsmecmd.2009.22.396 ◽

2009 ◽

Vol 2009.22 (0) ◽

pp. 396-397

Author(s):

Ryo KOBAYASHI ◽

Takahide NAKAMURA ◽

Shuji OGATA

Keyword(s):

Crack Propagation ◽

Particle Method ◽

Multiscale Simulation ◽

Coarse Grained

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Self-assembling dipeptides: conformational sampling in solvent-free coarse-grained simulation

Physical Chemistry Chemical Physics ◽

10.1039/b818144f ◽

2009 ◽

Vol 11 (12) ◽

pp. 2077 ◽

Cited By ~ 64

Author(s):

Alessandra Villa ◽

Christine Peter ◽

Nico F. A. van der Vegt

Keyword(s):

Solvent Free ◽

Coarse Grained ◽

Conformational Sampling ◽

Self Assembling

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Recent Advances in Coarse-Grained Models for Biomolecules and Their Applications

International Journal of Molecular Sciences ◽

10.3390/ijms20153774 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3774 ◽

Cited By ~ 10

Author(s):

Nidhi Singh ◽

Wenjin Li

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Self Assembly ◽

Structure Prediction ◽

Biological Systems ◽

Conformational Dynamics ◽

Multiscale Simulation ◽

Coarse Grained ◽

Hierarchical Level ◽

Dynamics Simulations

Molecular dynamics simulations have emerged as a powerful tool to study biological systems at varied length and timescales. The conventional all-atom molecular dynamics simulations are being used by the wider scientific community in routine to capture the conformational dynamics and local motions. In addition, recent developments in coarse-grained models have opened the way to study the macromolecular complexes for time scales up to milliseconds. In this review, we have discussed the principle, applicability and recent development in coarse-grained models for biological systems. The potential of coarse-grained simulation has been reviewed through state-of-the-art examples of protein folding and structure prediction, self-assembly of complexes, membrane systems and carbohydrates fiber models. The multiscale simulation approaches have also been discussed in the context of their emerging role in unravelling hierarchical level information of biosystems. We conclude this review with the future scope of coarse-grained simulations as a constantly evolving tool to capture the dynamics of biosystems.

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Distributed Multiscale Simulations of Clay-Polymer Nanocomposites

MRS Proceedings ◽

10.1557/opl.2012.1009 ◽

2012 ◽

Vol 1470 ◽

Cited By ~ 5

Author(s):

James Suter ◽

Derek Groen ◽

Lara Kabalan ◽

Peter V. Coveney

Keyword(s):

Polymer Nanocomposites ◽

System Size ◽

Multiscale Simulation ◽

Coarse Grained ◽

Mechanical Resistance ◽

Clay Platelet ◽

Length Scales ◽

Molecular Arrangement ◽

Wide Range ◽

Clay Platelets

ABSTRACTThe mechanical enhancement of polymers when clay nanoparticles are dispersed within it depends on factors over various length scales; for example, the orientation of the clay platelets in the polymer matrix will affect the mechanical resistance of the composite, while at the shortest scale the molecular arrangement and the adhesion energy of the polymer molecules in the galleries and the vicinity of the clay-polymer interface will also affect the overall mechanical properties.In this paper, we address the challenge of creating a hierarchal multiscale modelling scheme to traverse a sufficiently wide range of time and length scales to simulate clay-polymer nanocomposites effectively. This scheme varies from the electronic structure (to capture the polymer – clay interactions, especially those of the reactive clay edges) through classical atomistic molecular dynamics to coarse-grained models (to capture the long length scale structure).Such a scenario is well suited to distributed computing with each level of the scheme allocated to a suitable computational resource. We describe how the e-infrastructure and tools developed by the MAPPER (Multiscale Applications on European e-Infrastructures) project facilitates our multiscale scheme. Using this new technology, we have simulated clay-polymer systems containing up to several million atoms/particles. This system size is firmly within the mesoscopic regime, containing several clay platelets with the edges of the platelets explicitly resolved. We show preliminary results of a “bottom-up” multiscale simulation of a clay platelet dispersion in poly(ethylene) glycol.

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