Transferable Mixing of Atomistic and Coarse-Grained Water Models

Dual-resolution approaches for molecular simulations combine the best of two worlds, providing atomic details in regions of interest and coarser but much faster descriptions of less-relevant parts of molecular systems. Given the abundance of water in biomolecular systems, reducing the computational cost of simulating bulk water without perturbing the solute’s properties is a very attractive strategy. Here we show that the coarse-grained model for water called WatFour (WT4) can be combined with any of the three most used water models for atomistic simulations (SPC, TIP3P, and SPC/E) without modifying the characteristics of the atomistic solvent and solutes. The equivalence of fully atomistic and hybrid solvation approaches is assessed by comparative simulations of pure water, electrolyte solutions, and the β1 domain of streptococcal protein G, for which comparisons between experimental and calculated chemical shifts at ¹³Cα are equivalent

Mixing Atomistic and Coarse Grain Solvation Models for MD Simulations: Let WT4 Handle the Bulk

Accurate simulation of biomolecular systems requires the consideration of solvation effects. The arrangement and dynamics of water close to a solute are strongly influenced by the solute itself. However, as the solute–solvent distance increases, the water properties tend to those of the bulk liquid. This suggests that bulk regions can be treated at a coarse grained (CG) level, while keeping the atomistic details around the solute. Since water represents about 80% of any biological system, this approach may offer a significant reduction in the computational cost of simulations without compromising atomistic details. We show here that mixing the popular SPC water model with a CG model for solvation (called WatFour) can effectively mimic the hydration, structure, and dynamics of molecular systems composed of pure water, simple electrolyte solutions, and solvated macromolecules. As a nontrivial example, we present simulations of the SNARE membrane fusion complex, a trimeric protein–protein complex embedded in a double phospholipid bilayer. Comparison with a fully atomistic reference simulation illustrates the equivalence between both approaches

Molecular Dynamics Study of the Interaction of Arginine with Phosphatidylcholine and Phosphatidylethanolamine Bilayers

In this work, the differential interaction of zwitterionic arginines with fully hydrated dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) bilayers was analyzed by molecular dynamics simulations. In both systems, arginine binds to lipids with the carboxylate moiety oriented toward the aqueous phase, in agreement with previous experimental determinations of ζ potential of DMPC and DMPE liposomes. The guanidinium groups are found at different depths within the bilayers indicating that some arginines are buried, especially in DMPE. We observe, in the DMPE system, that the strongest interaction occurs between the guanidinium group and the carbonyl oxygen of the lipid. In the case of DMPC membranes, the strongest interaction is found between the guanidinium groups of the arginines and the phosphate groups of the lipids. Unexpectedly, arginine zwitterions are stabilized through the creation of hydrogen bonds (HB), either with water or with polar groups of the lipids. The mechanisms of interaction seem to be different in both membranes. In DMPE bilayers, arginines insert by breaking the inner HB network of the polar head groups, consequently increasing the occupied area per lipid molecule. In the DMPC bilayers the arginines insert by replacing the already present water molecules within the membrane, without significant effects on the area per lipid

Video_1_Cues to Opening Mechanisms From in Silico Electric Field Excitation of Cx26 Hemichannel and in Vitro Mutagenesis Studies in HeLa Transfectans.AVI

<p>Connexin channels play numerous essential roles in virtually every organ by mediating solute exchange between adjacent cells, or between cytoplasm and extracellular milieu. Our understanding of the structure-function relationship of connexin channels relies on X-ray crystallographic data for human connexin 26 (hCx26) intercellular gap junction channels. Comparison of experimental data and molecular dynamics simulations suggests that the published structures represent neither fully-open nor closed configurations. To facilitate the search for alternative stable configurations, we developed a coarse grained (CG) molecular model of the hCx26 hemichannel and studied its responses to external electric fields. When challenged by a field of 0.06 V/nm, the hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second transmembrane helix (TM2) at the level of the conserved Pro87. A point mutation that inhibited such transition in our simulations impeded hemichannel opening in electrophysiology and dye uptake experiments conducted on HeLa tranfectants. These results suggest that the hCx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among the whole connexin family.</p

Image_1_Cues to Opening Mechanisms From in Silico Electric Field Excitation of Cx26 Hemichannel and in Vitro Mutagenesis Studies in HeLa Transfectans.PNG

<p>Connexin channels play numerous essential roles in virtually every organ by mediating solute exchange between adjacent cells, or between cytoplasm and extracellular milieu. Our understanding of the structure-function relationship of connexin channels relies on X-ray crystallographic data for human connexin 26 (hCx26) intercellular gap junction channels. Comparison of experimental data and molecular dynamics simulations suggests that the published structures represent neither fully-open nor closed configurations. To facilitate the search for alternative stable configurations, we developed a coarse grained (CG) molecular model of the hCx26 hemichannel and studied its responses to external electric fields. When challenged by a field of 0.06 V/nm, the hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second transmembrane helix (TM2) at the level of the conserved Pro87. A point mutation that inhibited such transition in our simulations impeded hemichannel opening in electrophysiology and dye uptake experiments conducted on HeLa tranfectants. These results suggest that the hCx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among the whole connexin family.</p

Protein and solvent models of the MD simulations.

<p><b>A.</b> The whole system contained in an icosahedral box. Clipped TrV capsid representation with viral proteins colored in blue for VP1, green for VP2 and red for VP3. Water molecules are represented as a continuous surface, ice blue for atomistic SPC waters, cyan for coarse-grain WT4 beads and transparent cyan for coarse-grain WLS (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006082#pcbi.1006082.s004" target="_blank">S3 Fig</a>). <b>B.</b> Side view of the clipped TrV capsid penton (5xVP1-3) in a surface representation (proteins are colored with the same code as in A). <b>C.</b> Simplified representation of the pore found along the five-fold symmetry axis of the TrV capsid. Amino acids lining the cavity are represented as sticks (green are polar amino acids and yellow are non-polar). The main chain of the polypeptide is sketched in light blue. The internal narrowest region of the cavity is shown as a green surface, and the wider pore regions with a diameter up to ca. 0.9 nm are colored blue. Inset: The TrV capsid is composed of 12 pentamers, each composed of 5xVP1-3 proteins. The white dashed line indicates the frontier of one pentamer (or <i>penton</i>).</p

Video_2_p31-43 Gliadin Peptide Forms Oligomers and Induces NLRP3 Inflammasome/Caspase 1- Dependent Mucosal Damage in Small Intestine.MP4

<p>Celiac disease (CD) is a chronic enteropathy elicited by a Th1 response to gluten peptides in the small intestine of genetically susceptible individuals. However, it remains unclear what drives the induction of inflammatory responses of this kind against harmless antigens in food. In a recent work, we have shown that the p31-43 peptide (p31-43) from α-gliadin can induce an innate immune response in the intestine and that this may initiate pathological adaptive immunity. The receptors and mechanisms responsible for the induction of innate immunity by p31-43 are unknown and here we present evidence that this may reflect conformational changes in the peptide that allow it to activate the NLRP3 inflammasome. Administration of p31-43, but not scrambled or inverted peptides, to normal mice induced enteropathy in the proximal small intestine, associated with increased production of type I interferon and mature IL-1β. P31-43 showed a sequence-specific spontaneous ability to form structured oligomers and aggregates in vitro and induced activation of the ASC speck complex. In parallel, the enteropathy induced by p31-43 in vivo did not occur in the absence of NLRP3 or caspase 1 and was inhibited by administration of the caspase 1 inhibitor Ac-YVAD-cmk. Collectively, these findings show that p31-43 gliadin has an intrinsic propensity to form oligomers which trigger the NLRP3 inflammasome and that this pathway is required for intestinal inflammation and pathology when p31-43 is administered orally to mice. This innate activation of the inflammasome may have important implications in the initial stages of CD pathogenesis.</p

CG modeling of the TrV capsid and electrostatic destabilization.

<p><b>A.</b> RMSD (top) and the gyration radius (bottom) calculated for the amino acid alpha carbon positions along the MD trajectory. The RMSD of the entire capsid and one single penton are presented in gray and green, respectively. <b>B.</b> Gyration radii of the capsid loaded with increasing amounts of Cl^- in the interior. The number of anions is indicated in each curve by the same color. <b>C.</b> Molecular representation of the destabilized capsid. Solvent and pentons in the front and back of the plane are semitransparent for improved visualization. The remaining pentons are depicted in different colors. The inset illustrates the preferential separation between pentons that allows the exit of Cl^-. <b>D.</b> Protein-protein contacts monitored along the simulation containing under extreme conditions 1600 Cl^- within the capsid core (corresponding to an internal charge density of 2.3x10^-4 e^-/ų). Inter-penton and intra-penton contacts are presented in gray and green, respectively.</p

Proton migration through a Grotthuss-like mechanism.

<p>The hydration promoted by the ion located in the five-fold cavity allows proton migration through the cavity. Protein atoms are indicated by a stick model with red and blue segments. Oxygens from water (H₂O) are denoted by small red spheres, and oxygen from hydroxyl ions (OH^-) are large red spheres. Solvent protons are small white spheres, and protein protons are white sticks. The Mg²⁺ is highlighted as a green sphere. Panels A-G show the sequence of events used for the QM calculations for proton transport induced by a pH gradient. Four OH^- located in the outer solvent region represent a high pH relative to the capsid inner solvent region. Red arrows point to the position of OH^- at each step of the simulation, and these points correspond to the H⁺ hole jumping stepwise from the top to the bottom. The yellow arrow indicates the water coordinated to the metal ion that participates in the inner part of the water wire. Panel E corresponds to the transition state (TS) between configurations D and F, in which the H⁺ hole overcomes a low energy barrier towards the capsid interior. Lower panels show the distances (in Å) at each step between the atoms participating in the proton transfer. For clarity, only a subset of the 536 atoms involved in the calculation was included in these panels.</p

Schematic representations of the Grotthuss and Grotthuss-like mechanism for proton channeling.

<p>The amino acid labels indicated on the right side serve as positional references. The Mg²⁺ (green sphere) is coordinated with three water molecules and three Oε1 side chain oxygen atoms based on the symmetry-related Gln 3014 (green circles). <b>A.</b> When the external capsid pH is basic with to respect the internal region, protons jump between adjacent waters as indicated by the arrows. Under this condition, H⁺ holes can migrate from the capsid exterior (overcoming a low energetic barrier), showing a concerted Grotthuss-like mechanism of proton jumps. This sequence corresponds to panels A-G of <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006082#pcbi.1006082.g003" target="_blank">Fig 3</a>. <b>B.</b> When the outer solvent region is acidic with respect to the capsid interior (higher hydronium concentration), proton migration occurs between hydronium and H₂O molecules. A proton that binds to a hydronium in the upper bulk solvent can go down two steps along the external portion of the water wire (ΔE ~ -4.2 kcal/mol). When this proton migration occurs, it stops at the water close to the water molecule coordinated to the Mg²⁺. From this point down, the water wire is disrupted due to the increase in distance between the hydronium and the inner-most proximal water molecule (~0.36 nm), which is precisely the one linked to the metal cation. Breaking of the water wire constitutes the electrical impediment for the proton to proceed downward and reach the capsid internal solvent. Positive and negative numbers indicate the approximate energy value (in kcal) that corresponds to each proton jump. For clarity, only a subset of the 536 atoms involved in the calculation was included in these panels.</p