scholarly journals Coarse-grained implicit solvent lipid force field with a compatible resolution to the Cα protein representation

2020 ◽  
Author(s):  
Diego Ugarte La Torre ◽  
Shoji Takada
Keyword(s):  
Biological Membrane ◽  
Md Simulations ◽  
Membrane Dynamics ◽  
Phospholipid Bilayer ◽  
Coarse Grained ◽  
Implicit Solvent ◽  
Membrane Bilayer ◽  
Area Per Lipid ◽  
Phase Behaviors ◽  
Protein Models

AbstractBiological membranes have been prominent targets for coarse-grained (CG) molecular dynamics (MD) simulations. While minimal CG lipid models with three-beads per lipid and quantitative CG lipid models with >10-beads per lipid have been well studied, in between them, CG lipid models with a compatible resolution to residue-level CG protein models are much less developed. Here, we extended a previously developed three-bead lipid model into a five-bead model and parametrized it for two phospholipids, POPC and DPPC. The developed model, iSoLF, reproduced the area per lipid, hydrophobic thickness, and phase behaviors of the target phospholipid bilayer membranes at the physiological temperature. The model POPC and DPPC membranes were in liquid and gel phases, respectively, in accordance with experiments. We further examined the spontaneous formation of a membrane bilayer, the temperature dependence of physical properties, vesicle dynamics, and the POPC/DPPC two-component membrane dynamics of the CG lipid model, showing some promise. Once combined with standard Cα protein models, the iSoLF model will be a powerful tool to simulate large biological membrane systems made of lipids and proteins.

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 Thermodynamics and free energy landscape of BAR-domain dimerization from molecular simulations

2020 ◽  
Author(s):  
Adip Jhaveri ◽  
Dhruw Maisuria ◽  
Matthew Varga ◽  
Dariush Mohammadyani ◽  
Margaret E Johnson
Keyword(s):  
Free Energy ◽  
Energy Surface ◽  
Md Simulations ◽  
Coarse Grained ◽  
Enhanced Sampling ◽  
Free Energies ◽  
Free Energy Surface ◽  
Bar Domain ◽  
Bar Domains ◽  
Protein Models

AbstractNearly all proteins interact specifically with other proteins, often forming reversible bound structures whose stability is critical to function. Proteins with BAR domains function to bind to, bend, and remodel biological membranes, where the dimerization of BAR domains is a key step in this function. Here we characterize the binding thermodynamics of homodimerization between the LSP1 BAR domain proteins in solution, using Molecular Dynamics (MD) simulations. By combining the MARTINI coarse-grained protein models with enhanced sampling through metadynamics, we construct a two-dimensional free energy surface quantifying the bound versus unbound ensembles as a function of two distance variables. Our simulations portray a heterogeneous and extraordinarily stable bound ensemble for these modeled LSP1 proteins. The proper crystal structure dimer has a large hydrophobic interface that is part of a stable minima on the free energy surface, which is enthalpically the minima of all bound structures. However, we also find several other stable nonspecific dimers with comparable free energies to the specific dimer. Through structure-based clustering of these bound structures, we find that some of these ‘nonspecific’ contacts involve extended tail regions that help stabilize the higher-order oligomers formed by BAR-domains, contacts that are separated from the homodimer interface. We find that the known membrane-binding residues of the LSP1 proteins rarely participate in any of the bound interfaces, but that both patches of residues are aligned to interact with the membrane in the specific dimer. Hence, we would expect a strong selection of the specific dimer in binding to the membrane. The effect of a 100mM NaCl buffer reduces the relative stability of nonspecific dimers compared to the specific dimer, indicating that it would help prevent aggregation of the proteins. With these results, we provide the first free energy characterization of interaction pathways in this important class of membrane sculpting domains, revealing a variety of interfacial contacts outside of the specific dimer that may help stabilize its oligomeric assemblies.

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 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.

How do mechanosensitive channels sense membrane tension?

2016 ◽  
Vol 44 (4) ◽  
pp. 1019-1025 ◽  
Author(s):  
Tim Rasmussen
Keyword(s):  
Membrane Lipids ◽  
Osmotic Shock ◽  
Md Simulations ◽  
Fatty Acyl ◽  
Membrane Bilayer ◽  
Cross Sectional ◽  
Conducting Path ◽  
Lipid Chain ◽  
Acyl Chains

Mechanosensitive (MS) channels provide protection against hypo-osmotic shock in bacteria whereas eukaryotic MS channels fulfil a multitude of important functions beside osmoregulation. Interactions with the membrane lipids are responsible for the sensing of mechanical force for most known MS channels. It emerged recently that not only prokaryotic, but also eukaryotic, MS channels are able to directly sense the tension in the membrane bilayer without any additional cofactor. If the membrane is solely viewed as a continuous medium with specific anisotropic physical properties, the sensitivity towards tension changes can be explained as result of the hydrophobic coupling between membrane and transmembrane (TM) regions of the channel. The increased cross-sectional area of the MS channel in the active conformation and elastic deformations of the membrane close to the channel have been described as important factors. However, recent studies suggest that molecular interactions of lipids with the channels could play an important role in mechanosensation. Pockets in between TM helices were identified in the MS channel of small conductance (MscS) and YnaI that are filled with lipids. Less lipids are present in the open state of MscS than the closed according to MD simulations. Thus it was suggested that exclusion of lipid fatty acyl chains from these pockets, as a consequence of increased tension, would trigger gating. Similarly, in the eukaryotic MS channel TRAAK it was found that a lipid chain blocks the conducting path in the closed state. The role of these specific lipid interactions in mechanosensation are highlighted in this review.

VERIFICATION OF THE GENERALIZED BORN MODEL AT SHORT DISTANCES

2013 ◽  
Vol 13 (06) ◽  
pp. 1340020
Author(s):  
XIAOCHUAN TANG ◽  
YONG DUAN
Keyword(s):  
Analytical Solutions ◽  
Md Simulations ◽  
Solvation Energy ◽  
Implicit Solvent ◽  
Generalized Born ◽  
Simple Description ◽  
Born Model ◽  
Solvent Models ◽  
Potential Methods ◽  
Gb Model

The generalized Born (GB) model, one of the implicit solvent models, is widely applied in molecular dynamics (MD) simulations as a simple description of the solvation effect. In the GB model, an empirical function called the Still's formula, with the algorithmic simplicity, is utilized to calculate the solvation energy due to the polarization, termed as ΔG pol . Applications of the GB model have exhibited reasonable accuracy and high computational efficiency. However, there is still room for improvements. Most of the attempts to improve the GB model focus on optimizing effective Born radii. Contrarily, limited researches have been performed to improve the feasibility of the Still's formula. In this paper, analytical methods was applied to investigate the validity of the Still's formula at short distance. Taking advantage of the toroidal coordinates and Mehler–Fock transform, the analytical solutions of the GB model at short distances was derived explicitly for the first time. Additionally, the solvation energy was numerically computed using proper algorithms based on the analytical solutions and compared with ΔG pol calculated in the GB model. With the analysis on the deficiencies of the Still's formula at short distances, potential methods to improve the validity of the GB model were discussed.

scholarly journals Dynamical Behavior and Conformational Selection Mechanism of the Intrinsically Disordered Sic1 Kinase-Inhibitor Domain

Life ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 110 ◽  
Author(s):  
Davide Sala ◽  
Ugo Cosentino ◽  
Anna Ranaudo ◽  
Claudio Greco ◽  
Giorgio Moro
Keyword(s):  
Kinase Inhibitor ◽  
Dynamical Behavior ◽  
Md Simulations ◽  
Molecular Shape ◽  
Conformational Space ◽  
Coarse Grained ◽  
Conformational Ensemble ◽  
Selection Mechanism ◽  
Conformational Selection ◽  
Intrinsically Disordered

Intrinsically Disordered Peptides and Proteins (IDPs) in solution can span a broad range of conformations that often are hard to characterize by both experimental and computational methods. However, obtaining a significant representation of the conformational space is important to understand mechanisms underlying protein functions such as partner recognition. In this work, we investigated the behavior of the Sic1 Kinase-Inhibitor Domain (KID) in solution by Molecular Dynamics (MD) simulations. Our results point out that application of common descriptors of molecular shape such as Solvent Accessible Surface (SAS) area can lead to misleading outcomes. Instead, more appropriate molecular descriptors can be used to define 3D structures. In particular, we exploited Weighted Holistic Invariant Molecular (WHIM) descriptors to get a coarse-grained but accurate definition of the variegated Sic1 KID conformational ensemble. We found that Sic1 is able to form a variable amount of folded structures even in absence of partners. Among them, there were some conformations very close to the structure that Sic1 is supposed to assume in the binding with its physiological complexes. Therefore, our results support the hypothesis that this protein relies on the conformational selection mechanism to recognize the correct molecular partners.

scholarly journals Biophysical characterization of the SARS-CoV-2 E protein

2021 ◽  
Author(s):  
Aujan Mehregan ◽  
Sergio Perez-Conesa ◽  
Yuxuan Zhuang ◽  
Ahmad Elbahnsi ◽  
Diletta Pasini ◽  
...  
Keyword(s):  
Recombinant Expression ◽  
Structural Data ◽  
Md Simulations ◽  
Full Length ◽  
Coarse Grained ◽  
Biophysical Characterization ◽  
Viral Budding ◽  
Nmr Structures ◽  
E Protein

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic which continues to wreak havoc across the world, over a year and a half after its effects were first reported in the general media. Current fundamental research efforts largely focus on the SARS-CoV-2 Spike protein. Since successful antiviral therapies are likely to target multiple viral components, there is considerable interest in understanding the biophysical role of its other proteins, in particular structural membrane proteins. Here, we have focused our efforts on the characterization of the full-length E protein from SARS-CoV-2, combining experimental and computational approaches. Recombinant expression of the full-length E protein from SARS-CoV-2 reveals that this membrane protein is capable of independent multimerization, possibly as a tetrameric or smaller species. Fluorescence microscopy shows that the protein localizes intracellularly, and coarse-grained MD simulations indicate it causes bending of the surrounding lipid bilayer, corroborating a potential role for the E protein in viral budding. Although we did not find robust electrophysiological evidence of ion-channel activity, cells transfected with the E protein exhibited reduced intracellular Ca2+, which may further promote viral replication. However, our atomistic MD simulations revealed that previous NMR structures are relatively unstable, and result in models incapable of ion conduction. Our study highlights the importance of using high-resolution structural data obtained from a full-length protein to gain detailed molecular insights, and eventually permitting virtual drug screening.

scholarly journals Residue-Level Contact Reveals Modular Domain Interactions of PICK1 Are Driven by Both Electrostatic and Hydrophobic Forces

2021 ◽  
Vol 7 ◽  
Author(s):  
Amy O. Stevens ◽  
Yi He
Keyword(s):  
Hydrophobic Interactions ◽  
Pdz Domain ◽  
Md Simulations ◽  
Intramolecular Interactions ◽  
Coarse Grained ◽  
Scaffolding Protein ◽  
Concave Surface ◽  
Stable Complex ◽  
Bar Domain ◽  
C Terminus

PICK1 is a multi-domain scaffolding protein that is uniquely comprised of both a PDZ domain and a BAR domain. While previous experiments have shown that the PDZ domain and the linker positively regulate the BAR domain and the C-terminus negatively regulates the BAR domain, the details of internal regulation mechanisms are unknown. Molecular dynamics (MD) simulations have been proven to be a useful tool in revealing the intramolecular interactions at atomic-level resolution. PICK1 performs its biological functions in a dimeric form which is extremely computationally demanding to simulate with an all-atom force field. Here, we use coarse-grained MD simulations to expose the key residues and driving forces in the internal regulations of PICK1. While the PDZ and BAR domains do not form a stable complex, our simulations show the PDZ domain preferentially interacting with the concave surface of the BAR domain over other BAR domain regions. Furthermore, our simulations show that the short helix in the linker region can form interactions with the PDZ domain. Our results reveal that the surface of the βB-βC loop, βC strand, and αA-βD loop of the PDZ domain can form a group of hydrophobic interactions surrounding the linker helix. These interactions are driven by hydrophobic forces. In contrast, our simulations reveal a very dynamic C-terminus that most often resides on the convex surface of the BAR domain rather than the previously suspected concave surface. These interactions are driven by a combination of electrostatic and hydrophobic interactions.

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