scholarly journals Mesoscale computational protocols for the design of highly cooperative bivalent macromolecules

2019 ◽  
Author(s):  
S. Saurabh ◽  
F. Piazza
Keyword(s):  
Large Scale ◽  
Real Life ◽  
Computational Design ◽  
Md Simulations ◽  
Coarse Grained ◽  
Immune Synapse ◽  
Multi Scale ◽  
Therapeutic Molecules ◽  
Potentials Of Mean Force ◽  
Design Protocol

ABSTRACTThe last decade has witnessed a swiftly increasing interest in the design and production of novel multivalent molecules as powerful alternatives for conventional antibodies in the fight against cancer and infectious diseases. However, while it is widely accepted that large-scale flexibility (10 − 100 nm) and free/constrained dynamics (100 ns −µs) control the activity of such novel molecules, computational strategies at the mesoscale still lag behind experiments in optimizing the design of crucial features, such as the binding cooperativity (a.k.a. avidity).In this study, we introduced different coarse-grained models of a polymer-linked, two-nanobody composite molecule, with the aim of laying down the physical bases of a thorough computational drug design protocol at the mesoscale. We show that the calculation of suitable potentials of mean force allows one to apprehend the nature, range and strength of the thermodynamic forces that govern the motion of free and wall-tethered molecules. Furthermore, we develop a simple computational strategy to quantify the encounter/dissociation dynamics between the free end of a wall-tethered molecule and the surface, at the roots of binding cooperativity. This procedure allows one to pinpoint the role of internal flexibility and weak non-specific interactions on the kinetic constants of the NB-wall encounter and dissociation. Finally, we quantify the role and weight of rare events, which are expected to play a major role in real-life situations, such as in the immune synapse, where the binding kinetics is likely dominated by fluctuations.SIGNIFICANCEMultivalent and multispecific molecules composed of polymer-linked nanobodies have gained interest as engineered alternatives to conventional antibodies. These therapeutic molecules have a larger reach due to their smaller size and promise substantial and tunable gains in avidity. This paper studies a model diabody to lay the bases of a multi-scale computational design of the structural and dynamical determinants of binding cooperativity, rooted in a blend of atomistic and coarse-grained MD simulations and concepts from statistical mechanics.

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 Multiscale Modeling of Amyloid Fibrils Formed by Aggregating Peptides Derived from the Amyloidogenic Fragment of the A-Chain of Insulin

2021 ◽  
Vol 22 (22) ◽  
pp. 12325
Author(s):  
Michał Koliński ◽  
Robert Dec ◽  
Wojciech Dzwolak
Keyword(s):  
Structure Prediction ◽  
Amyloid Fibrils ◽  
Md Simulations ◽  
Molecular Structures ◽  
Coarse Grained ◽  
Multi Scale ◽  
Modeling Procedure ◽  
Scale Modeling ◽  
Multi Scale Modeling ◽  
A Chain

Computational prediction of molecular structures of amyloid fibrils remains an exceedingly challenging task. In this work, we propose a multi-scale modeling procedure for the structure prediction of amyloid fibrils formed by the association of ACC1-13 aggregation-prone peptides derived from the N-terminal region of insulin’s A-chain. First, a large number of protofilament models composed of five copies of interacting ACC1-13 peptides were predicted by application of CABS-dock coarse-grained (CG) docking simulations. Next, the models were reconstructed to all-atom (AA) representations and refined during molecular dynamics (MD) simulations in explicit solvent. The top-scored protofilament models, selected using symmetry criteria, were used for the assembly of long fibril structures. Finally, the amyloid fibril models resulting from the AA MD simulations were compared with atomic force microscopy (AFM) imaging experimental data. The obtained results indicate that the proposed multi-scale modeling procedure is capable of predicting protofilaments with high accuracy and may be applied for structure prediction and analysis of other amyloid fibrils.

scholarly journals Why a Large-Scale Mode Can Be Essential for Understanding Intracellular Actin Waves

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1533 ◽  
Author(s):  
Carsten Beta ◽  
Nir S. Gov ◽  
Arik Yochelis
Keyword(s):  
Large Scale ◽  
Mass Conservation ◽  
Coarse Grained ◽  
Cellular Functions ◽  
Multi Scale ◽  
Spatio Temporal ◽  
Actin Waves ◽  
Inhibitor Type ◽  
Activator Inhibitor Type

During the last decade, intracellular actin waves have attracted much attention due to their essential role in various cellular functions, ranging from motility to cytokinesis. Experimental methods have advanced significantly and can capture the dynamics of actin waves over a large range of spatio-temporal scales. However, the corresponding coarse-grained theory mostly avoids the full complexity of this multi-scale phenomenon. In this perspective, we focus on a minimal continuum model of activator–inhibitor type and highlight the qualitative role of mass conservation, which is typically overlooked. Specifically, our interest is to connect between the mathematical mechanisms of pattern formation in the presence of a large-scale mode, due to mass conservation, and distinct behaviors of actin waves.

scholarly journals Constant pH simulations with the coarse-grained MARTINI model — Application to oleic acid aggregates

2013 ◽  
Vol 91 (9) ◽  
pp. 839-846 ◽  
Author(s):  
W.F. Drew Bennett ◽  
Alexander W. Chen ◽  
Serena Donnini ◽  
Gerrit Groenhof ◽  
D. Peter Tieleman
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Phase Behavior ◽  
Large Scale ◽  
Md Simulations ◽  
Industrial Applications ◽  
Coarse Grained ◽  
Head Group ◽  
Constant Ph ◽  
Surfactant Phase

Long chain fatty acids are biologically important molecules with complex and pH sensitive aggregation behavior. The carboxylic head group of oleic acid is ionizable, with the pKa shifting to larger values, even above a value of 7, in certain aggregate states. While experiments have determined the macroscopic phase behavior, we have yet to understand the molecular level details for this complex behavior. This level of detail is likely required to fully appreciate the role of fatty acids in biology and for nanoscale biotechnological and industrial applications. Here, we introduce the use of constant pH molecular dynamics (MD) simulations with the coarse-grained MARTINI model and apply the method to oleic acid aggregates and a model lipid bilayer. By running simulations at different constant pH values, we determined titration curves and the resulting pKa for oleic acid in different environments. The coarse-grained model predicts positive pKa shifts, with a shift from 4.8 in water to 6.5 in a small micelle, and 6.6 in a dioleoylphosphatidylcholine (DOPC) bilayer, similar to experimental estimates. The size of the micelles increased as the pH increased, and correlated with the fraction of deprotonated oleic acid. We show this combination of constant pH MD and the coarse-grained MARTINI model can be used to model pH-dependent surfactant phase behavior. This suggests a large number of potential new applications of large-scale MARTINI simulations in other biological systems with ionizable molecules.

scholarly journals Explicit and implicit modeling of nanobubbles in hydrophobic confinement

2010 ◽  
Vol 82 (1) ◽  
pp. 3-12 ◽  
Author(s):  
Joachim Dzubiella
Keyword(s):  
Large Scale ◽  
Md Simulations ◽  
Energy Functional ◽  
Coarse Grained ◽  
Implicit Solvent ◽  
Implicit Solvent Model ◽  
Solvent Model ◽  
Nanofluidic Devices ◽  
Capillary Evaporation ◽  
Hydrophobic Solutes

Water at normal conditions is a fluid thermodynamically close to the liquid-vapor phase coexistence and features a large surface tension. This combination can lead to interesting capillary phenomena on microscopic scales. Explicit water molecular dynamics (MD) computer simulations of hydrophobic solutes, for instance, give evidence of capillary evaporation on nanometer scales, i.e., the formation of nanometer-sized vapor bubbles (nanobubbles) between confining hydrophobic surfaces. This phenomenon has been exemplified for solutes with varying complexity, e.g., paraffin plates, coarse-grained homopolymers, biological and solid-state channels, and atomistically resolved proteins. It has been argued that nanobubbles strongly impact interactions in nanofluidic devices, translocation processes, and even in protein stability, function, and folding. As large-scale MD simulations are computationally expensive, the efficient multiscale modeling of nanobubbles and the prediction of their stability poses a formidable task to the'nanophysical' community. Recently, we have presented a conceptually novel and versatile implicit solvent model, namely, the variational implicit solvent model (VISM), which is based on a geometric energy functional. As reviewed here, first solvation studies of simple hydrophobic solutes using VISM coupled with the numerical level-set scheme show promising results, and, in particular, capture nanobubble formation and its subtle competition to local energetic potentials in hydrophobic confinement.

scholarly journals Capturing Protein-Ligand Recognition Pathways in Coarse-grained Simulation

2019 ◽  
Author(s):  
Bhupendra R. Dandekar ◽  
Jagannath Mondal
Keyword(s):  
Large Scale ◽  
Computational Cost ◽  
Md Simulations ◽  
Coarse Grained ◽  
Attractive Alternative ◽  
Complex Process ◽  
Potential Binding ◽  
Allosteric Sites ◽  
Potential Binding Site ◽  
Complete Process

AbstractProtein-substrate recognition is highly dynamic and complex process in nature. A key approach in deciphering the mechanism underlying the recognition process is to capture the kinetic process of substrate in its act of binding to its designated protein cavity. Towards this end, microsecond long atomistic molecular dynamics (MD) simulation has recently emerged as a popular method of choice, due its ability to record these events at high spatial and temporal resolution. However, success in this approach comes at an exorbitant computational cost. Here we demonstrate that coarse grained models of protein, when systematically optimised to maintain its tertiary fold, can capture the complete process of spontaneous protein-ligand binding from bulk media to cavity, within orders of magnitude shorter wall clock time compared to that of all-atom MD simulations. The simulated and crystallographic binding pose are in excellent agreement. We find that the exhaustive sampling of ligand exploration in protein and solvent, harnessed by coarse-grained simulation at a frugal computational cost, in combination with Markov state modelling, leads to clearer mechanistic insights and discovery of novel recognition pathways. The result is successfully validated against three popular protein-ligand systems. Overall, the approach provides an affordable and attractive alternative of all-atom simulation and promises a way-forward for replacing traditional docking based small molecule discovery by high-throughput coarse-grained simulation for searching potential binding site and allosteric sites. This also provides practical avenues for first-hand exploration of bio-molecular recognition processes in large-scale biological systems, otherwise inaccessible in all-atom simulations.

scholarly journals A glimpse of fluid turbulence from the molecular scale

2014 ◽  
Vol 25 (08) ◽  
pp. 1450034 ◽  
Author(s):  
Teruhisa S. Komatsu ◽  
Shigenori Matsumoto ◽  
Takashi Shimada ◽  
Nobuyasu Ito
Keyword(s):  
Large Scale ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Md Simulations ◽  
Energy Dissipation Rate ◽  
Coarse Grained ◽  
Fluid Turbulence ◽  
Molecular Scale ◽  
Decaying Turbulence ◽  
Three Dimensional Space

Large-scale molecular dynamics (MD) simulations of freely decaying turbulence in three-dimensional space are reported. Fluid components are defined from the microscopic states by eliminating thermal components from the coarse-grained fields. The energy spectrum of the fluid components is observed to scale reasonably well according to Kolmogorov scaling determined from the energy dissipation rate and the viscosity of the fluid, even though the Kolmogorov length is of the order of the molecular scale.

scholarly journals The Assembly Switch Mechanism of FtsZ Filament Revealed by All-Atom Molecular Dynamics Simulations and Coarse-Grained Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Dashuai Lv ◽  
Jingyuan Li ◽  
Sheng Ye
Keyword(s):  
Molecular Dynamics ◽  
Bound States ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Coarse Grained ◽  
Multi Scale ◽  
Switch Mechanism ◽  
Dynamics Simulations ◽  
Cooperative Assembly ◽  
Computational Strategy

Bacterial cytoskeletal protein FtsZ binds and hydrolyzes GTP, and assembles into dynamic filaments that are essential for cell division. Here, we used a multi-scale computational strategy that combined all-atom molecular dynamics (MD) simulations and coarse-grained models to reveal the conformational dynamics of assembled FtsZ. We found that the top end of a filament is highly dynamic and can undergo T-to-R transitions in both GTP- and GDP-bound states. We observed several subcategories of nucleation related dimer species, which leading to a feasible nucleation pathway. In addition, we observed that FtsZ filament exhibits noticeable amounts of twisting, indicating a substantial helicity of the FtsZ filament. These results agree with the previously models and experimental data. Anisotropy network model (ANM) analysis revealed a polymerization enhanced assembly cooperativity, and indicated that the cooperative motions in FtsZ are encoded in the structure. Taken together, our study provides a molecular-level understanding of the diversity of the structural states of FtsZ and the relationships among polymerization, hydrolysis, and cooperative assembly, which should shed new light on the molecular basis of FtsZ’s cooperativity.

scholarly journals Multi-Scale Flexible Fitting of Proteins to Cryo-EM Density Maps at Medium Resolution

2021 ◽  
Vol 8 ◽  
Author(s):  
Marta Kulik ◽  
Takaharu Mori ◽  
Yuji Sugita
Keyword(s):  
Md Simulations ◽  
Conformational Transitions ◽  
Force Constants ◽  
Coarse Grained ◽  
Implicit Solvent ◽  
Multi Scale ◽  
Cryo Electron Microscopy ◽  
Density Maps ◽  
Medium Resolution ◽  
Density Map

Structure determination using cryo-electron microscopy (cryo-EM) medium-resolution density maps is often facilitated by flexible fitting. Avoiding overfitting, adjusting force constants driving the structure to the density map, and emulating complex conformational transitions are major concerns in the fitting. To address them, we develop a new method based on a three-step multi-scale protocol. First, flexible fitting molecular dynamics (MD) simulations with coarse-grained structure-based force field and replica-exchange scheme between different force constants replicas are performed. Second, fitted Cα atom positions guide the all-atom structure in targeted MD. Finally, the all-atom flexible fitting refinement in implicit solvent adjusts the positions of the side chains in the density map. Final models obtained via the multi-scale protocol are significantly better resolved and more reliable in comparison with long all-atom flexible fitting simulations. The protocol is useful for multi-domain systems with intricate structural transitions as it preserves the secondary structure of single domains.

scholarly journals Public Awareness: What Climate Change Scientists Should Consider

2020 ◽  
Vol 12 (20) ◽  
pp. 8369
Author(s):  
Mohammad Rahimi
Keyword(s):  
Climate Change ◽  
Social Media ◽  
Large Scale ◽  
Public Awareness ◽  
Connected Network ◽  
Multi Scale ◽  
Valuable Addition ◽  
Scientific Approach ◽  
Design Solutions ◽  
Mitigate Climate Change

In this Opinion, the importance of public awareness to design solutions to mitigate climate change issues is highlighted. A large-scale acknowledgment of the climate change consequences has great potential to build social momentum. Momentum, in turn, builds motivation and demand, which can be leveraged to develop a multi-scale strategy to tackle the issue. The pursuit of public awareness is a valuable addition to the scientific approach to addressing climate change issues. The Opinion is concluded by providing strategies on how to effectively raise public awareness on climate change-related topics through an integrated, well-connected network of mavens (e.g., scientists) and connectors (e.g., social media influencers).

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