Prediction of the 1H and 13C NMR spectra of alpha-D-glucose in water by DFT methods and MD simulations

We have applied computational protocols based on DFT and molecular dynamics simulations to the prediction of the alkyl 1H and 13C chemical shifts of alpha-d-glucose in water. Computed data have been compared with accurate experimental chemical shifts obtained in our laboratory. 13C chemical shifts do not show a marked solvent effect. In contrast, the results for 1H chemical shifts provided by structures optimized in the gas phase are only fair and point out that it is necessary to take into account both the flexibility of the glucose structure and the strong effect exerted by solvent water thereupon. Thus, molecular dynamics simulations were carried out to model both the internal geometry as well as the influence of solvent molecules on the conformational distribution of the solute. Snapshots from the simulation were used as input to DFT NMR calculations with varying degrees of sophistication. The most important factor that affects the accuracy of computed 1H chemical shifts is the solute geometry; the effect of the solvent on the shielding constants can be reasonably accounted for by self-consistent reaction field models without the need of explicitly including solvent molecules in the NMR property calculation.     

Computational study of enantioseparation by amylose tris(3,5‐dimethylphenylcarbamate)‐based chiral stationary phase

The mechanism of chiral separation on amylose tris(3,5‐dimethylphenylcarbamate) is studied with docking simulations of enantiomers by molecular dynamics. All‐atom models of amylose tris(3,5‐dimethylphenylcarbamate) on the modified silica gel surface were constructed for the docking simulations of metalaxyl and benalaxyl. The elution orders and energetic differences were also predicted based on the intermolecular interactions, which were in agreement with the experimental results. The radial distribution function was employed to analyze the structural features of the enantiomer‐chiral stationary phase complex and used to elucidate the mechanism of chiral separation. The separation of metalaxyl and benalaxyl is mainly controlled by the hydrogen bond. And the binding sites had slight differences for the pair of enantiomers, but obvious differences between different chemicals.     

Temperature‐Dependent Atomic Models of Detergent Micelles Refined against Small‐Angle X‐Ray Scattering Data

Surfactants have found a wide range of industrial and scientific applications. In particular, detergent micelles are used as lipid membrane mimics to solubilize membrane proteins for functional and structural characterization. However, an atomic‐level understanding of surfactants remains limited because many experiments provide only low‐resolution structural information on surfactant aggregates. In this work, small‐angle X‐ray scattering is combined with molecular dynamics simulations to derive fully atomic models of two maltoside micelles at temperatures between 10 °C and 70 °C. The micelles take the shape of general tri‐axial ellipsoids and decrease in size and aggregation number with increasing temperature. Density profiles of hydrophobic groups and water along the three principal axes reveal that the minor micelle axis closely mimics lipid membranes. The results suggest that coupling atomic simulations with low‐resolution data allows the structural characterization of surfactant aggregates.     

Increasing the time step with mass scaling in Born‐Oppenheimer ab initio QM/MM molecular dynamics simulations

Born‐Oppenheimer ab initio QM/MM molecular dynamics simulation with umbrella sampling is a state‐of‐the‐art approach to calculate free energy profiles of chemical reactions in complex systems. To further improve its computational efficiency, a mass‐scaling method with the increased time step in MD simulations has been explored and tested. It is found that by increasing the hydrogen mass to 10 amu, a time step of 3 fs can be employed in ab initio QM/MM MD simulations. In all our three test cases, including two solution reactions and one enzyme reaction, the resulted reaction free energy profiles with 3 fs time step and mass scaling are found to be in excellent agreement with the corresponding simulation results using 1 fs time step and the normal mass. These results indicate that for Born‐Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, the mass‐scaling method can significantly reduce its computational cost while has little effect on the calculated free energy profiles. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

Quantum mechanical/molecular mechanical simulation study of the mechanism of hairpin ribozyme catalysis

The molecular mechanism of hairpin ribozyme catalysis is studied with molecular dynamics simulations using a combined quantum mechanical and molecular mechanical (QM/MM) potential with a recently developed semiempirical AM1/d-PhoT model for phosphoryl transfer reactions. Simulations are used to derive one- and two-dimensional potentials of mean force to examine specific reaction paths and assess the feasibility of proposed general acid and base mechanisms. Density-functional calculations of truncated active site models provide complementary insight to the simulation results. Key factors utilized by the hairpin ribozyme to enhance the rate of transphosphorylation are presented, and the roles of A38 and G8 as general acid and base catalysts are discussed. The computational results are consistent with available experimental data, provide support for a general acid/base mechanism played by functional groups on the nucleobases, and offer important insight into the ability of RNA to act as a catalyst without explicit participation by divalent metal ions.     

Approximating nonequilibrium processes using a collection of surrogate diffusion models

The surrogate process approximation (SPA) is applied to model the nonequilibrium dynamics of a reaction coordinate (RC) associated with the unfolding and refolding processes of a deca-alanine peptide at 300 K. The RC dynamics, which correspond to the evolution of the end-to-end distance of the polypeptide, are produced by steered molecular dynamics (SMD) simulations and approximated using overdamped diffusion models. We show that the collection of (estimated) SPA models contain structural information "orthogonal" to the RC monitored in this study. Functional data analysis ideas are used to correlate functions associated with the fitted SPA models with the work done on the system in SMD simulations. It is demonstrated that the shape of the nonequilibrium work distributions for the unfolding and refolding processes of deca-alanine can be predicted with functional data analysis ideas using a relatively small number of simulated SMD paths for calibrating the SPA diffusion models.     

FMO‐MD Simulations on the Hydration of Formaldehyde in Water Solution with Constraint Dynamics

Full‐quantum mechanical fragment molecular orbital‐based molecular dynamics (FMO‐MD) simulations were applied to the hydration reaction of formaldehyde in water solution under neutral conditions. Two mechanisms, a concerted and a stepwise one, were considered with respect to the nucleophilic addition and the proton transfer. Preliminary molecular orbital calculations by means of polarized continuum model reaction field predicted that the hydration prefers a concerted mechanism. Because the calculated activation barriers were too high for free FMO‐MD simulations to give reactive trajectories spontaneously, a More O’Ferrall–Jencks‐type diagram was constructed from the statistical analysis of the FMO‐MD simulations with constraint dynamics. The diagram showed that the hydration proceeds through a zwitterionic‐like (ZW‐like) structure. The free energy changes along the reaction coordinate calculated by means of the blue moon ensemble for the hydration and the amination of formaldehyde indicated that the hydration proceeds through a concerted process through the ZW‐like structure, whereas the amination goes through a stepwise mechanism with a ZW intermediate. In inspection of the FMO‐MD trajectories, water‐mediated cyclic proton transfers were observed in both reactions on the way from the ZW‐like structure to the product. These proton transfers also have an asynchronous character, in which deprotonation from the nucleophilic oxygen atom (or nitrogen atom for amination) precedes the protonation of the carbonyl oxygen atom. The results showed the strong advantage of the FMO‐MD simulations to obtain detailed information at a molecular level for solution reactions.     

Theoretical study on photooxidation mechanism of ruthenium complex [Ru(II)‐(bpy)2(TMBiimH2)]2+ with molecular oxygen

Photoinduced reactions of ruthenium complexes with molecular oxygen have attracted a lot of experimental attention; however, the reaction mechanism remains elusive. In this work, we have used the density functional theory method to scrutinize the visible‐light induced photooxidation mechanism of the ruthenium complex [Ru(II)‐(bpy)₂(TMBiimH₂)]²⁺ (bpy: 2, 2‐bipyridine and TMBiimH₂: 4, 5, 4, 5‐tetramethyl‐2, 2‐biimidazole) initiated by the attack of molecular oxygen. The present computational results not only explain very well recent experiments, also provide new mechanistic insights. We found that: (1) the triplet energy transfer process between the triplet molecular oxygen and the metal‐ligand charge transfer triplet state of the ruthenium complex, which leads to singlet molecular oxygen, is thermodynamically favorable; (2) the singlet oxygen addition process to the S₀ ruthenium complex is facile in energy; (3) the chemical transformation from endoperoxide to epidioxetane intermediates can be either two‐ or one‐step reaction (the latter is energetically favored). These findings contribute important mechanistic information to photooxidation reactions of ruthenium complexes with molecular oxygen. © 2016 Wiley Periodicals, Inc.     

Using one‐step perturbation to predict the effect of changing force‐field parameters on the simulated folding equilibrium of a β‐peptide in solution

Computer simulation using molecular dynamics is increasingly used to simulate the folding equilibria of peptides and small proteins. Yet, the quality of the obtained results depends largely on the quality of the force field used. This comprises the solute as well as the solvent model and their energetic and entropic compatibility. It is, however, computational very expensive to perform test simulations for each combination of force‐field parameters. Here, we use the one‐step perturbation technique to predict the change of the free enthalpy of folding of a β‐peptide in methanol solution due to changing a variety of force‐field parameters. The results show that changing the solute backbone partial charges affects the folding equilibrium, whereas this is relatively insensitive to changes in the force constants of the torsional energy terms of the force field. Extending the cut‐off distance for nonbonded interactions beyond 1.4 nm does not affect the folding equilibrium. The same result is found for a change of the reaction‐field permittivity for methanol from 17.7 to 30. The results are not sensitive to the criterion, e.g., atom‐positional RMSD or number of hydrogen bonds, that is used to distinguish folded and unfolded conformations. Control simulations with perturbed Hamiltonians followed by backward one‐step perturbation indicated that quite large perturbations still yield reliable results. Yet, perturbing all solvent molecules showed where the limitations of the one‐step perturbation technique are met. The evaluated methodology constitutes an efficient tool in force‐field development for molecular simulation by reducing the number of required separate simulations by orders of magnitude. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Comparing reduced partial charge models with polarizable simulations of ionic liquids

Molecular ionic liquids are typically characterized by strong electrostatic interactions resulting in a charge ordering and retardation of their translational and rotational behaviour. Unfortunately, this effect is often overestimated in classical molecular dynamics simulations. This can be circumvented in a twofold way: the easiest way is to reduce the partial charges of the ions to sub-integer values of ±0.7-0.9 e. The more realistic model is to include polarizable forces, e.g. Drude-oscillators, but it comes along with an increasing computational effort. On the other hand, charge-scaled models are claimed to take an average polarizability into account. But do both models have the same impact on structure and dynamics of molecular ionic liquids? In the present study several molecular dynamics simulations of 1-ethyl-3-methylimidazolium trifluoromethanesulfonate are performed with different levels of polarization as well as with varying charge scaling factors of 0.74 to 0.90. The analysis of the structural and dynamical results are performed in different levels: from the atomic point of view over the molecular level to collective properties determined by the complete sample.     

Unraveling the Role of Water in the Stereoselective Step of Aqueous Proline‐Catalyzed Aldol Reactions

A multiscale computational study was performed with the aim of tracing the source of stereoselectivity and disclosing the role of water in the stereoselective step of propionaldehyde aldol self‐condensation catalyzed by proline amide in water, a reaction that serves as a model for aqueous organocatalytic aldol condensations. Solvent mixing and hydration behavior were assessed by classical molecular dynamics simulations, which show that the reaction between propanal and the corresponding enamine takes place in a fully hydrated environment. First‐principles molecular dynamics simulations were used to study the free‐energy profile of four possible reaction paths, each of which yields a different stereoisomer, and high‐level static first‐principles calculations were employed to characterize the transition states for microsolvated species. The first solvation shell of the oxygen atom of the electrophilic aldehyde at the transition states contains two water molecules, each of which donates one hydrogen bond to the nascent alkoxide and thereby largely stabilizes its excess electron density. The stereoselectivity originates in an extra hydrogen bond donated by the amido group of proline amide in two reaction paths.     

Lattice microbes: High‐performance stochastic simulation method for the reaction‐diffusion master equation

Spatial stochastic simulation is a valuable technique for studying reactions in biological systems. With the availability of high‐performance computing (HPC), the method is poised to allow integration of data from structural, single‐molecule and biochemical studies into coherent computational models of cells. Here, we introduce the Lattice Microbes software package for simulating such cell models on HPC systems. The software performs either well‐stirred or spatially resolved stochastic simulations with approximated cytoplasmic crowding in a fast and efficient manner. Our new algorithm efficiently samples the reaction‐diffusion master equation using NVIDIA graphics processing units and is shown to be two orders of magnitude faster than exact sampling for large systems while maintaining an accuracy of ～ 0.1%. Display of cell models and animation of reaction trajectories involving millions of molecules is facilitated using a plug‐in to the popular VMD visualization platform. The Lattice Microbes software is open source and available for download at http://www.scs.illinois.edu/schulten/lm © 2012 Wiley Periodicals, Inc.     

Ordering surfaces on the nanoscale: implications for protein adsorption

Monolayer-protected metal nanoparticles (MPMNs) are a newly discovered class of nanoparticles with an ordered, striped domain structure that can be readily manipulated by altering the ratio of the hydrophobic to hydrophilic ligands. This property makes them uniquely suited to systematic studies of the role of nanostructuring on biomolecule adsorption, a phenomenon of paramount importance in biomaterials design. In this work, we examine the interaction of the simple, globular protein cytochrome C (Cyt C) with MPMN surfaces using experimental protein assays and computational molecular dynamics simulations. Experimental assays revealed that adsorption of Cyt C generally increased with increasing surface polar ligand content, indicative of the dominance of hydrophilic interactions in Cyt C-MPMN binding. Protein-surface adsorption enthalpies calculated from computational simulations employing rigid-backbone coarse-grained Cyt C and MPMN models indicate a monotonic increase in adsorption enthalpy with respect to MPMN surface polarity. These results are in qualitative agreement with experimental results and suggest that Cyt C does not undergo significant structural disruption upon adsorption to MPMN surfaces. Coarse-grained and atomistic simulations furthermore elucidated the important role of lysine in facilitating Cyt C adsorption to MPMN surfaces. The amphipathic character of the lysine side chain enables it to form close contacts with both polar and nonpolar surface ligands simultaneously, rendering it especially important for interactions with surfaces composed of adjacent nanoscale chemical domains. The importance of these structural characteristics of lysine suggests that proteins may be engineered to specifically interact with nanomaterials by targeted incorporation of unnatural amino acids possessing dual affinity to differing chemical motifs.     

Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 1. Generalized Born

We present an implementation of generalized Born implicit solvent all-atom classical molecular dynamics (MD) within the AMBER program package that runs entirely on CUDA enabled NVIDIA graphics processing units (GPUs). We discuss the algorithms that are used to exploit the processing power of the GPUs and show the performance that can be achieved in comparison to simulations on conventional CPU clusters. The implementation supports three different precision models in which the contributions to the forces are calculated in single precision floating point arithmetic but accumulated in double precision (SPDP), or everything is computed in single precision (SPSP) or double precision (DPDP). In addition to performance, we have focused on understanding the implications of the different precision models on the outcome of implicit solvent MD simulations. We show results for a range of tests including the accuracy of single point force evaluations and energy conservation as well as structural properties pertainining to protein dynamics. The numerical noise due to rounding errors within the SPSP precision model is sufficiently large to lead to an accumulation of errors which can result in unphysical trajectories for long time scale simulations. We recommend the use of the mixed-precision SPDP model since the numerical results obtained are comparable with those of the full double precision DPDP model and the reference double precision CPU implementation but at significantly reduced computational cost. Our implementation provides performance for GB simulations on a single desktop that is on par with, and in some cases exceeds, that of traditional supercomputers.     

Elucidating the origin of diastereoselectivity in a self-replicating system: selfishness versus altruism

We have investigated a diastereoselective self‐replicating system based on a cycloaddition of a fulvene derivative and a maleimide using a two‐pronged approach of combining NMR spectroscopy with computational modelling. Two diastereomers are formed with identical rates in the absence of replication. When replication is enabled, one diastereomer takes over the resources as a “selfish” autocatalyst, while exploiting the competitor as a weak “altruist”, resulting in a diastereoselectivity of 16:1. We applied 1D and 2D NMR spectroscopic techniques supported by ab initio chemical shifts as well as ab initio molecular dynamics simulations to study the structure and dynamics of the underlying network. This powerful combination allowed us to decipher the energetic and structural rationale behind the observed behaviour, while static computational methods currently used in the field did not.     

Temperature rising elution fractionation, infra red and rheology study on gamma irradiated HMSPP

It is well known that polypropylene undergoes simultaneous crosslinking and degradation under irradiation. However, there are speculations regarding the formation of branching under special conditions. It is also well known that the melt-strength property of a polymer increases with molecular weight and with long-chain branching due to the increase in the entanglement level. This study was a contribution to the understanding of the following points: the role of molecular weight, the role of structural modifications on nucleation properties; the structural changes on polypropylene.

The results showed that degradation was the major reaction in the initial step of irradiation, however, the largely modified molecules concentrated in the high molecular weight fraction. The results also confirm that the branching formation is likely to occur.     

Single‐Crystal Cobalt Phosphate Nanosheets for Biomimetic Oxygen Evolution in Neutral Electrolytes

To improve energy conversion efficiency, the development of active electrocatalysts with similar structural features to photosynthesis II systems (PS‐II), which can efficiently catalyze the oxygen evolution reaction (OER), have received great research interest. Crystalline cobalt phosphate nanosheets are designed as an efficient OER catalyst in neutral media, showing outstanding performance that even outperforms the noble RuO₂ benchmark. The correlation of experimental and computational results reveals that the active sites are the edge‐sharing CoO₉ structural motif, akin to the molecular geometry of PS‐II. This unique structure can facilitate reaction intermediate adsorption and decrease the reaction energy barrier, thus improving the OER kinetics.     

Impact of graphene-based nanomaterials (GBNMs) on the structural and functional conformations of hepcidin peptide

Graphene-based nanomaterials (GBNMs) are widely used in various industrial and biomedical applications. GBNMs of different compositions, size and shapes are being introduced without thorough toxicity evaluation due to the unavailability of regulatory guidelines. Computational toxicity prediction methods are used by regulatory bodies to quickly assess health hazards caused by newer materials. Due to increasing demand of GBNMs in various size and functional groups in industrial and consumer based applications, rapid and reliable computational toxicity assessment methods are urgently needed. In the present work, we investigate the impact of graphene and graphene oxide nanomaterials on the structural conformations of small hepcidin peptide and compare the materials for their structural and conformational changes. Our molecular dynamics simulation studies revealed conformational changes in hepcidin due to its interaction with GBMNs, which results in a loss of its functional properties. Our results indicate that hepcidin peptide undergo severe structural deformations when superimposed on the graphene sheet in comparison to graphene oxide sheet. These observations suggest that graphene is more toxic than a graphene oxide nanosheet of similar area. Overall, this study indicates that computational methods based on structural deformation, using molecular dynamics (MD) simulations, can be used for the early evaluation of toxicity potential of novel nanomaterials.