120 research outputs found
Coupling Coarse-Grained to Fine-Grained Models via Hamiltonian Replica Exchange
The energy landscape of biomolecular systems contains many local minima that are separated by high energy barriers. Sampling this landscape in molecular dynamics simulations is a challenging task, and often requires the use of enhanced sampling techniques. Here, we increase the sampling efficiency by coupling the fine-grained (FG) GROMOS force field to the coarse-grained (CG) Martini force field via the Hamiltonian replica exchange method (HREM). We tested the efficiency of this procedure using a lutein/octane system. In traditional simulations, cis-trans transitions of lutein are barely observed due to the high energy barrier separating these states. However, many of these transitions are sampled with our HREM scheme. The proposed method offers new possibilities for enhanced sampling of biomolecular conformations, making use of CG models without compromising the accuracy of the FG model
Dual Resolution Membrane Simulations Using Virtual Sites
All-atomistic (AA) and coarse-grain (CG) simulations have been successfully applied to investigate a broad range of biomolecular processes. However, the accessible time and length scales of AA simulation are limited and the specific molecular details of CG simulation are simplified. Here, we propose a virtual site (VS) based hybrid scheme that can concurrently couple AA and CG resolutions in a single membrane simulation, mitigating the shortcomings of either representation. With some adjustments to make the AA and CG force fields compatible, we demonstrate that lipid bilayer properties are well kept in our hybrid approach. Our VS hybrid method was also applied to simulate a small lipid vesicle, with the inner leaflet and interior solvent represented in AA, and the outer leaflet together with exterior solvent at the CG level. Our multiscale method opens the way to investigate biomembrane properties at increased computational efficiency, in particular applications involving large solvent filled regions
Interactive Molecular Dynamics in Virtual Reality Is an Effective Tool for Flexible Substrate and Inhibitor Docking to the SARS-CoV-2 Main Protease
Interactivity:the missing link between virtual reality technology and drug discovery pipelines
The potential of virtual reality (VR) to contribute to drug design and
development has been recognised for many years. Hardware and software
developments now mean that this potential is beginning to be realised, and VR
methods are being actively used in this sphere. A recent advance is to use VR
not only to visualise and interact with molecular structures, but also to
interact with molecular dynamics simulations of 'on the fly' (interactive
molecular dynamics in VR, IMD-VR), which is useful not only for flexible
docking but also to examine binding processes and conformational changes.
iMD-VR has been shown to be useful for creating complexes of ligands bound to
target proteins, e.g., recently applied to peptide inhibitors of the SARS-CoV-2
main protease. In this review, we use the term 'interactive VR' to refer to
software where interactivity is an inherent part of the user VR experience
e.g., in making structural modifications or interacting with a physically
rigorous molecular dynamics (MD) simulation, as opposed to simply using VR
controllers to rotate and translate the molecule for enhanced visualisation.
Here, we describe these methods and their application to problems relevant to
drug discovery, highlighting the possibilities that they offer in this arena.
We suggest that the ease of viewing and manipulating molecular structures and
dynamics, and the ability to modify structures on the fly (e.g., adding or
deleting atoms) makes modern interactive VR a valuable tool to add to the
armoury of drug development methods.Comment: 19 pages, 3 figure
PBxplore: a tool to analyze local protein structure and deformability with Protein Blocks
This paper describes the development and application of a suite of tools, called PBxplore, to analyze the dynamics and deformability of protein structures using Protein Blocks (PBs). Proteins are highly dynamic macromolecules, and a classical way to analyze their inherent flexibility is to perform molecular dynamics simulations. The advantage of using small structural prototypes such as PBs is to give a good approximation of the local structure of the protein backbone. More importantly, by reducing the conformational complexity of protein structures, PBs allow analysis of local protein deformability which cannot be done with other methods and had been used efficiently in different applications. PBxplore is able to process large amounts of data such as those produced by molecular dynamics simulations. It produces frequencies, entropy and information logo outputs as text and graphics. PBxplore is available at https://github.com/pierrepo/PBxplore and is released under the open-source MIT license
Resolving Donor-Acceptor Interfaces and Charge Carrier Energy Levels of Organic Semiconductors with Polar Side Chains
Organic semiconductors consisting of molecules bearing polar side chains have been proposed as potential candidates to overcome the limitations of organic photovoltaics owing to their enhanced dielectric constant. However, introducing such polar molecules in photovoltaic devices has not yet resulted in higher efficiencies. A microscopic understanding of the impact of polar side chains on electronic and structural properties of organic semiconductors is paramount to rationalize their effect. Here, the impact of such side chains on bulk heterojunction overall morphology, molecular configurations at donor-acceptor (DA) interfaces, and charge carrier energy levels is investigated. The multiscale modeling approach used allows to resolve DA interfaces with atomistic resolution while taking into account the large-scale self-organization process which takes place during the processing of an organic thin film. The polar fullerene-based blends are compared to the well-studied reference system, poly(3-hexyl-thiophene) (P3HT):phenyl-C-61-butyric acid methyl ester (PCBM). Introduction of polar side chains on a similar molecular scaffold does not affect molecular orientations at the DA interfaces; such orientations are, however, found to be affected by processing conditions and polymer molecular weight. Polar side chains, instead, are found to impact considerably the charge carrier energy levels of the organic blend, causing electrostatic-induced broadening of these levels
Martini 3 Coarse-Grained Force Field:Small Molecules
The recent re-parametrization of the Martini coarse-grained force field, Martini 3, improved the accuracy of the model in predicting molecular packing and interactions in molecular dynamics simulations. Here, we describe how small molecules can be accurately parametrized within the Martini 3 framework and present a database of validated small molecule models. We pay particular attention to the description of aliphatic and aromatic ring-like structures, which are ubiquitous in small molecules such as solvents and drugs or in building blocks constituting macromolecules such as proteins and synthetic polymers. In Martini 3, ring-like structures are described by models that use higher resolution coarse-grained particles (small and tiny particles). As such, the present database constitutes one of the cornerstones of the calibration of the new Martini 3 small and tiny particle sizes. The models show excellent partitioning behavior and solvent properties. Miscibility trends between different bulk phases are also captured, completing the set of thermodynamic properties considered during the parametrization. We also show how the new bead sizes allow for a good representation of molecular volume, which translates into better structural properties such as stacking distances. We further present design strategies to build Martini 3 models for small molecules of increased complexity
Free energy along drug-protein binding pathways interactively sampled in virtual reality
We describe a two-step approach for combining interactive molecular dynamics
in virtual reality (iMD-VR) with free energy (FE) calculation to explore the
dynamics of biological processes at the molecular level. We refer to this
combined approach as iMD-VR-FE. Stage one involves using a state-of-the-art
iMD-VR framework to generate a diverse range of protein-ligand unbinding
pathways, benefitting from the sophistication of human spatial and chemical
intuition. Stage two involves using the iMD-VR-sampled pathways as initial
guesses for defining a path-based reaction coordinate from which we can obtain
a corresponding free energy profile using FE methods. To investigate the
performance of the method, we apply iMD-VR-FE to investigate the unbinding of a
benzamidine ligand from a trypsin protein. The binding free energy calculated
using iMD-VR-FE is similar for each pathway, indicating internal consistency.
Moreover, the resulting free energy profiles can distinguish energetic
differences between pathways corresponding to various protein-ligand
conformations (e.g., helping to identify pathways that are more favourable) and
enable identification of metastable states along the pathways. The two-step
iMD-VR-FE approach offers an intuitive way for researchers to test hypotheses
for candidate pathways in biomolecular systems, quickly obtaining both
qualitative and quantitative insight
Piezo1 Forms Specific, Functionally Important Interactions with Phosphoinositides and Cholesterol
Touch, hearing, and blood pressure regulation require mechanically gated ion channels that convert mechanical stimuli into electrical currents. One such channel is Piezo1, which plays a key role in the transduction of mechanical stimuli in humans and is implicated in diseases, such as xerocytosis and lymphatic dysplasia. There is building evidence that suggests Piezo1 can be regulated by the membrane environment, with the activity of the channel determined by the local concentration of lipids, such as cholesterol and phosphoinositides. To better understand the interaction of Piezo1 with its environment, we conduct simulations of the protein in a complex mammalian bilayer containing more than 60 different lipid types together with electrophysiology and mutagenesis experiments. We find that the protein alters its local membrane composition, enriching specific lipids and forming essential binding sites for phosphoinositides and cholesterol that are functionally relevant and often related to Piezo1-mediated pathologies. We also identify a number of key structural connections between the propeller and pore domains located close to lipid-binding sites
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