Presence Of Explicit Solvent Research Articles

Understanding the conformational changes in the influenza B M2 ion channel at various protonation states

The characterization of influenza (A/B M2) ion channels is very important as they are potential binding sites for the drugs. We report the all-atom molecular dynamics study of the influenza B M2 ion channel in the presence of explicit solvent and lipid bilayers using the high resolution solid-state NMR structures. The importance of the various protonation states of histidine in the activation of the ion channel is discussed. The conformational changes at the closed and the open structures clearly show that the increase in tilt angle is necessary for the activation of the ion channel. Additionally, the free energy surfaces of the eight systems show the importance of the protonation state of the histidine residues in the activation of the influenza B M2 ion channel. The protonation of the histidine residues increases the tilt angle and the intra-helix distance which is evident from the superimposition of the structures corresponding to the maxima and the minima in the free energy landscape. The findings imply differences in the singly protonated and double protonated conformational states of BM2 ion channel and provide insights to help further studies of these ion channels as the drug targets for the influenza virus.

Artificial Intelligence and QM/MM with a Polarizable Reactive Force Field for Next-Generation Electrocatalysts

<h2>Summary</h2> To develop new generations of electrocatalysts, we need the accuracy of full explicit solvent quantum mechanics (QM) for practical-sized nanoparticles and catalysts. To do this, we start with the RexPoN reactive force field that provides higher accuracy than density functional theory (DFT) for water and combine it with QM to accurately include long-range interactions and polarization effects to enable reactive simulations with QM accuracy in the presence of explicit solvent. We apply this RexPoN-embedded QM (ReQM) to reactive simulations of electrocatalysis, demonstrating that ReQM accurately replaces DFT water for computing the Raman frequencies of reaction intermediates during CO₂ reduction to ethylene. Then, we illustrate the power of this approach by combining with machine learning to predict the performance of about 10,000 surface sites and identify the active sites of solvated gold (Au) nanoparticles and dealloyed Au surfaces. This provides an accurate but practical way to design high-performance electrocatalysts.

A twist in the road less traveled: The AMBER ff15ipq-m force field for protein mimetics.

We present a new force field, AMBER ff15ipq-m, for simulations of protein mimetics in applications from therapeutics to biomaterials. This force field is an expansion of the AMBER ff15ipq force field that was developed for canonical proteins and enables the modeling of four classes of artificial backbone units that are commonly used alongside natural α residues in blended or "heterogeneous" backbones: chirality-reversed D-α-residues, the Cα-methylated α-residue Aib, homologated β-residues (β3) bearing proteinogenic side chains, and two cyclic β residues (βcyc; APC and ACPC). The ff15ipq-m force field includes 472 unique atomic charges and 148 unique torsion terms. Consistent with the AMBER IPolQ lineage of force fields, the charges were derived using the Implicitly Polarized Charge (IPolQ) scheme in the presence of explicit solvent. To our knowledge, no general force field reported to date models the combination of artificial building blocks examined here. In addition, we have derived Karplus coefficients for the calculation of backbone amide J-coupling constants for β3Ala and ACPC β residues. The AMBER ff15ipq-m force field reproduces experimentally observed J-coupling constants in simple tetrapeptides and maintains the expected conformational propensities in reported structures of proteins/peptides containing the artificial building blocks of interest-all on the μs timescale. These encouraging results demonstrate the power and robustness of the IPolQ lineage of force fields in modeling the structure and dynamics of natural proteins as well as mimetics with protein-inspired artificial backbones in atomic detail.

Development of transferable coarse-grained models of amino acids

We have developed transferable coarse-grained (CG) models of the twenty standard amino acids, which can be used to perform molecular dynamics (MD) simulations of peptide amphiphiles (PAs) in the presence of explicit solvent.

Tribological Behavior of Grafted Nanoparticle on Polymer-Brushed Walls: A Dissipative Particle Dynamics Study.

Two contacting surfaces grafted with polymer brushes have potential applications due to their extraordinary lubricating behavior. However, the polymer brushes may have poor mechanical stability under high normal and shear stresses, which is a challenge for practical usage of polymer brush systems. In this study, we propose the use of grafted nanoparticles as nanobearings on polymer-brush-coated surfaces to alleviate the harsh working conditions of polymer brushes and to improve their mechanical stability. We have performed dissipative particle dynamics (DPD) simulations to investigate the tribological interaction between grafted nanoparticle and parallel walls with noncharged polymer brushes in the presence of explicit solvent. The influences of several parameters (solvent quality, brush miscibility, etc.) on the tribological behavior of the system are investigated. The grafted nanoparticle obviously acts as a nanobearing that partially replaces the sliding contact between two brushed walls with rolling contact between the grafted nanoparticle and two brushed walls and reduces the number of DPD particles withstanding high force. Although the introduction of the grafted nanoparticle into polymer-brushed walls increases the friction coefficient by 20-30%, it does not greatly decrease lubrication of the brushed walls, while still helping in stabilizing the system of polymer brushes to be used with liquids with low viscosity, such as water. The DPD simulation results and analysis performed in this study would be beneficial in designing systems with polymer-brushed surfaces and grafted nanoparticles.

Combined Experimental and Simulation Studies of Cross-Linked Polymer Brushes under Shear.

We have studied the effect of cross-linking on the tribological behavior of polymer brushes using a combined experimental and theoretical approach. Tribological and indentation measurements on poly(glycidyl methacrylate) brushes and gels in the presence of dimethylformamide solvent were obtained by means of atomic force microscopy. To complement experiments, we have performed corresponding molecular dynamics (MD) simulations of a generic bead–spring model in the presence of explicit solvent and cross-linkers. Our study shows that cross-linking leads to an increase in friction between polymer brushes and a counter-surface. The coefficient of friction increases with increasing degree of cross-linking and decreases with increasing length of the cross-linker chains. We find that the brush-forming polymer chains in the outer layer play a significant role in reducing friction at the interface.

Free energy landscape of siRNA-polycation complexation: Elucidating the effect of molecular geometry, polymer flexibility, and charge neutralization

The success of medical threatments with DNA and silencing interference RNA is strongly related to the design of efficient delivery technologies. Cationic polymers represent an attractive strategy to serve as nucleic-acid carriers with the envisioned advantages of efficient complexation, low cost, ease of production, well-defined size, and low polydispersity index. However, the balance between efficacy and toxicity (safety) of these polymers is a challenge and in need of improvement. With the aim of designing more effective polycationic-based gene carriers, many parameters such as carrier morphology, size, molecular weight, surface chemistry, and flexibility/rigidity ratio need to be taken into consideration. In the present work, the binding mechanism of three cationic polymers (polyarginine, polylysine and polyethyleneimine) to a model siRNA target is computationally investigated at the atomistic level. In order to better understand the polycationic carrier-siRNA interactions, replica exchange molecular dynamic simulations were carried out to provide an exhaustive exploration of all the possible binding sites, taking fully into account the siRNA flexibility together with the presence of explicit solvent and ions. Moreover, well-tempered metadynamics simulations were employed to elucidate how molecular geometry, polycation flexibility, and charge neutralization affect the siRNA-polycations free energy landscape in term of low-energy binding modes and unbinding free energy barriers. Significant differences among polymer binding modes have been detected, revealing the advantageous binding properties of polyarginine and polylysine compared to polyethyleneimine.

Further along the Road Less Traveled: AMBER ff15ipq, an Original Protein Force Field Built on a Self-Consistent Physical Model

We present the AMBER ff15ipq force field for proteins, the second-generation force field developed using the Implicitly Polarized Q (IPolQ) scheme for deriving implicitly polarized atomic charges in the presence of explicit solvent. The ff15ipq force field is a complete rederivation including more than 300 unique atomic charges, 900 unique torsion terms, 60 new angle parameters, and new atomic radii for polar hydrogens. The atomic charges were derived in the context of the SPC/Eb water model, which yields more-accurate rotational diffusion of proteins and enables direct calculation of nuclear magnetic resonance (NMR) relaxation parameters from molecular dynamics simulations. The atomic radii improve the accuracy of modeling salt bridge interactions relative to contemporary fixed-charge force fields, rectifying a limitation of ff14ipq that resulted from its use of pair-specific Lennard-Jones radii. In addition, ff15ipq reproduces penta-alanine J-coupling constants exceptionally well, gives reasonable agreement with NMR relaxation rates, and maintains the expected conformational propensities of structured proteins/peptides, as well as disordered peptides—all on the microsecond (μs) time scale, which is a critical regime for drug design applications. These encouraging results demonstrate the power and robustness of our automated methods for deriving new force fields. All parameters described here and the mdgx program used to fit them are included in the AmberTools16 distribution.

Computing pK(A) values of hexa-aqua transition metal complexes.

Aqueous pKA values for 15 hexa-aqua transition metal complexes were computed using a combination of quantum chemical and electrostatic methods. Two different structure models were considered optimizing the isolated complexes in vacuum or in presence of explicit solvent using a QM/MM approach. They yield very good agreement with experimentally measured pKA values with an overall root mean square deviation of about 1 pH unit, excluding a single but different outlier for each of the two structure models. These outliers are hexa-aqua Cr(III) for the vacuum and hexa-aqua Mn(III) for the QM/MM structure model. Reasons leading to the deviations of the outlier complexes are partially explained. Compared to previous approaches from the same lab the precision of the method was systematically improved as discussed in this study. The refined methods to obtain the appropriate geometries of the complexes, developed in this work, may allow also the computation of accurate pKA values for multicore transition metal complexes in different oxidation states.

Thermodynamics of Deca-alanine Folding in Water

The determination of the folding dynamics of polypeptides and proteins is critical in characterizing their functions in biological systems. Numerous computational models and methods have been developed for studying structure formation at the atomic level. Due to its small size and simple structure, deca-alanine is used as a model system in molecular dynamics (MD) simulations. The free energy of unfolding in vacuum has been studied extensively using the end-to-end distance of the peptide as the reaction coordinate. However, few studies have been conducted in the presence of explicit solvent. Previous results show a significant decrease in the free energy of extended conformations in water, but the α-helical state is still notably favored over the extended state. Although sufficient in vacuum, we show that end-to-end distance is incapable of capturing the full complexity of deca-alanine folding in water. Using α-helical content as a second reaction coordinate, we deduce a more descriptive free-energy landscape, one which reveals a second energy minimum in the extended conformations that is of comparable free energy to the α-helical state. Equilibrium simulations demonstrate the relative stability of the extended and α-helical states in water as well as the transition between the two states. This work reveals both the necessity and challenge of determining a proper reaction coordinate to fully characterize a given process.

Probing the Flexibility of Tropomyosin and Its Binding to Filamentous Actin Using Molecular Dynamics Simulations

Tropomyosin (Tm) is a coiled-coil protein that binds to filamentous actin (F-actin) and regulates its interactions with actin-binding proteins like myosin by moving between three positions on F-actin (the blocked, closed, and open positions). To elucidate the molecular details of Tm flexibility in relation to its binding to F-actin, we conducted extensive molecular dynamics simulations for both Tm alone and Tm-F-actin complex in the presence of explicit solvent (total simulation time >400 ns). Based on the simulations, we systematically analyzed the local flexibility of the Tm coiled coil using multiple parameters. We found a good correlation between the regions with high local flexibility and a number of destabilizing regions in Tm, including six clusters of core alanines. Despite the stabilization by F-actin binding, the distribution of local flexibility in Tm is largely unchanged in the absence and presence of F-actin. Our simulations showed variable fluctuations of individual Tm periods from the closed position toward the open position. In addition, we performed Tm-F-actin binding calculations based on the simulation trajectories, which support the importance of Tm flexibility to Tm-F-actin binding. We identified key residues of Tm involved in its dynamic interactions with F-actin, many of which have been found in recent mutational studies to be functionally important, and the rest of which will make promising targets for future mutational experiments.

Characterizing the Pathway, Free Energy, and the Effect of Substrate Binding on Structural Transition of MFS Transporter GlpT between Inward- and Outward-Facing States

Glycerol-3-phosphate transporter (GlpT) is an MFS secondary transporter whose structure has been only solved in the apo inward-facing (IF) state. Despite extensive experimental and computational studies, the structure of the outward-facing (OF) and occluded states, an accurate description of the IF-OF transition pathway, and the associated energetics are missing. We have studied the IF-OF structural transition of GlpT using a novel approach based on a combination of several state-of-the-art sampling techniques such as nonequilibrium driven MD, umbrella sampling, and Hamiltonian replica exchange MD. Biasing the system along a set of system-specific holonomic coordinates allowed us to adequately sample the relevant regions of the phase space around the transition path in the presence of explicit solvent and membrane. The free energy profiles of the IF-OF transition were reconstructed for both the apo and the substrate-bound GlpT, using a novel implementation of the generalized weighted histogram analysis method (WHAM). Our results indicate that the known IF conformation is indeed the global minimum in the free energy profile of apo GlpT; however, there exists another low free energy minimum associated with an OF conformation with a free energy barrier of only 10 kcal/mol between the two states. More interestingly, the binding of a substrate not only lowers this barrier but also stabilizes at least two intermediate/occluded states that were not observed in the apo GlpT simulations. Our results not only verify the “alternating-access” mechanism but also provide a detailed description of the IF-OF transition mechanism of GlpT at an atomic level, establishing a quantitative basis for the study of MFS transporters and introducing a novel approach to study the large-scale transitions in membrane transporters.

Outward- to Inward-Facing Transition of MsbA Transporter: A Mechanistic Picture at Atomic Resolution

MsbA is a structurally well-characterized, bacterial ATP-binding cassette (ABC) exporter. It undergoes a large-scale conformational change between the inward-facing (IF) and the outward-facing (OF) states during its transport cycle. Despite extensive experimental and computational studies on MsbA and its homologs, a unified mechanistic picture describing the OF-IF conformational transition of ABC exporters is still missing. In order to study this transition at an atomic level, we have used a novel approach based on a nonequilibrium driven scheme and performed an extensive set of molecular dynamics simulations that sample the OF-to-IF reaction-path ensemble of the apo MsbA in the presence of explicit solvent and membrane. using several distinct system-specific biasing protocols, we were able to steer the system along a large number of different paths in a low-dimensional holonomic coordinate space. Nonequilibrium work relations were employed to interpret the results and to determine the optimal transition path. Our results provide clear evidence that the opening of the cytoplasmic gate in the apo MsbA is prohibitively disfavored when the extracellular gate is open, an observation consistent with the “alternating-access mechanism”. More interestingly, we observe that the closure of the extracellular gate does not result in a stable IF conformation unless the nucleotide-binding domains (NBDs) undergo a “twisting” motion that involves a drastic change in their relative orientation. We thus propose a “door-knob mechanism” for the OF-to-IF transition of MsbA that asserts a crucial role for the “twisting” of NBDs in the opening of the cytoplasmic gate. More generally, our results call into question the simplistic models of NBD dissociation/dimerization that ignore the important role of the relative orientation between the NBDs in promoting the OF-IF conformational transitions of ABC exporters.

Modeling the formation of ordered nano-assemblies comprised by dendrimers and linear polyelectrolytes: The role of Coulombic interactions

Models of mixtures of peripherally charged dendrimers with oppositely charged linear polyelectrolytes in the presence of explicit solvent are studied by means of molecular dynamics simulations. Under the influence of varying strength of electrostatic interactions, these systems appear to form dynamically arrested film-like interconnected structures in the polymer-rich phase. Acting like a pseudo-thermodynamic inverse temperature, the increase of the strength of the Coulombic interactions drive the polymeric constituents of the mixture to a gradual dynamic freezing-in. The timescale of the average density fluctuations of the formed complexes initially increases in the weak electrostatic regime reaching a finite limit as the strength of electrostatic interactions grow. Although the models are overall electrically neutral, during this process the dendrimer/linear complexes develop a polar character with an excess charge mainly close to the periphery of the dendrimers. The morphological characteristics of the resulted pattern are found to depend on the size of the polymer chains on account of the distinct conformational features assumed by the complexed linear polyelectrolytes of different length. In addition, the length of the polymer chain appears to affect the dynamics of the counterions, thus affecting the ionic transport properties of the system. It appears, therefore, that the strength of electrostatic interactions together with the length of the linear polyelectrolytes are parameters to which these systems are particularly responsive, offering thus the possibility for a better control of the resulted structure and the electric properties of these soft-colloidal systems.

Aminoglycoside induced nephrotoxicity: molecular modeling studies of calreticulin-gentamicin complex

Gentamicin is a member of aminoglycoside group of broad spectrum antibiotics. It impairs protein synthesis by binding to A site of the 30S subunit of bacterial ribosomes. One of the main side effects of this drug is nephrotoxicity. The drug is known to bind to calreticulin, a chaperone essential for the folding of glycosylated proteins. We provide a detailed structural insight of the calreticulin-gentamicin complex by molecular modeling and the binding of the drug in the presence of explicit solvent was analyzed by molecular dynamics simulation. The gentamicin molecule binds to the lectin site of the calreticulin and lies in the concave channel formed by the long beta sheets. It makes interactions with residues Tyr109, Asp125, Asp135, Asp317 and Trp319 which are crucial for the chaperone function of the calreticulin. The superimposing of the modeled complex with the only available crystal structure complex of calreticulin with a tetrasaccharide (Glc(1)Man(3)) shows interesting features. First, the rings of the gentamicin occupy the positions of glucose and the first two mannose sugars of the tetrasaccharide molecule. Second, the oxygen atoms of the glycosidic linkage of these two ligands have a positional deviation of 1.3 Ǻ. The predicted binding constant of 16.9 μM is in accordance with the previous kinetic study experiments. The details therefore, strongly implicate gentamicin as a competitive inhibitor of sugar binding with calreticulin.

Effects of Hydration on the Conformational Energy Landscape of the Pentapeptide Met-Enkephalin.

We report here a study of the conformational energy landscape of the pentapeptide Met-enkephalin in the presence of explicit solvent (water) molecules. A sample of 1 500 low-energy structures of this molecule was generated using the mutually orthogonal Latin squares (MOLS) technique with the CHARMM22 force field. This technique, developed in our laboratory, allows us to sample the conformational space of a molecule in an unbiased and exhaustive manner. The study shows that inclusion of explicit solvation is important to correctly model the conformational behavior of the molecule. Structures modeled in the presence of water molecules are far more similar to the experimental structures than when the water molecules are excluded. The results also indicate that the pentapeptide Met-enkephalin prefers extended structures in an aqueous environment, as against tightly folded structures in the absence of water. Thus, the biologically relevant structure, when the molecule is not bound to the receptor, is probably the extended structure, as seen in the crystallographic and NMR experiments, rather than the GEM structures calculated by various workers.

Self-Organization in Dendrimer Polyelectrolytes

Results from molecular dynamics simulations are reported, describing self-organization in solutions of charged dendrimer molecules upon variation of the strength of the electrostatic interactions, in the presence of explicit solvent and counterions. Systems of two sizes bearing different surface charge densities are studied at constant temperature and volume conditions. It is found that a systematic variation of Bjerrum length triggers a mechanism associated with counterion spatial correlations, which drives the systems from an amorphous liquidlike arrangement to an ordered state bearing the symmetry of a cubic phase. The role of dendrimer interpenetration, trapping of counterions, and solvent depletion in the ordering process is also explored. As this study employs a description which takes into account all the principal internal degrees of freedom of dendrimer molecules, the conclusions drawn are expected to offer a fair description of the behavior of realistic systems bearing similar dendritic topology.

Modeling Diffusion of Adsorbed Polymer with Explicit Solvent

Computer simulations of a polymer chain of length N strongly adsorbed at the solid-liquid interface in the presence of explicit solvent are used to delineate the factors affecting the N dependence of the polymer lateral diffusion coefficient, D(||). We find that surface roughness has a large influence, and D(||) scales as D(||) approximately N(-x), with x approximately 3/4 and x approximately 1 for ideal smooth and corrugated surfaces, respectively. The first result is consistent with the hydrodynamics of a "particle" of radius of gyration R(G) approximately N(nu) (nu=0.75) translating parallel to a planar interface, while the second implies that the friction of the adsorbed chains dominates. These results are discussed in the context of recent measurements.

Bending Elasticity of Anti-Parallel β-Sheets

Using a coarse-grained elastic model, we examine the bending properties of anti-parallel β-sheets comprised of uniform amino-acid residues in vacuum as well as in explicit solvent. By comparing the conformational probability of the β-sheet from molecular dynamics simulations with the same quantities obtained from the coarse-grained model, we compute the elastic bending constant, κ. Equilibrium fluctuations of the β-sheet and its response to external forces are well reproduced by a model with a uniform isotropic bending constant. An anisotropic bending model is also investigated, although the computed anisotropy is relatively weak and most of the observed properties are well described by an isotropic model. The presence of explicit solvent also lowers the bending constant. The sequence dependence of our result and its implications in protein conformational dynamics are discussed.

Enhanced sampling of peptide and protein conformations using replica exchange simulations with a peptide backbone biasing‐potential

During replica exchange molecular dynamics (RexMD) simulations, several replicas of a system are simulated at different temperatures in parallel allowing for exchange between replicas at frequent intervals. This technique allows significantly improved sampling of conformational space and is increasingly being used for structure prediction of peptides and proteins. A drawback of the standard temperature RexMD is the rapid increase of the replica number with increasing system size to cover a desired temperature range. In an effort to limit the number of replicas, a new Hamiltonian-RexMD method has been developed that is specifically designed to enhance the sampling of peptide and protein conformations by applying various levels of a backbone biasing potential for each replica run. The biasing potential lowers the barrier for backbone dihedral transitions and promotes enhanced peptide backbone transitions along the replica coordinate. The application on several peptide cases including in all cases explicit solvent indicates significantly improved conformational sampling when compared with standard MD simulations. This was achieved with a very modest number of 5-7 replicas for each simulation system making it ideally suited for peptide and protein folding simulations as well as refinement of protein model structures in the presence of explicit solvent.