Transannular Diels-Alder reactivities of 14-membered macrocylic trienes and their relationship with the conformational preferences of the reactants: a combined quantum chemical and molecular dynamics study

Transannular Diels-Alder (TADA) reactions that occur between the diene and dienophile moieties located on a single macrocyclic triene molecule have been recognized as effective synthetic routes toward realizing complex tricyclic molecules in a single step. In this paper, we report a comprehensive study on the TADA reactions of 14-membered cyclic triene macrocycles to yield A.B.C[6.6.6] tricycles using quantum chemical methods and using classical molecular dynamics simulations. A benchmark study has been performed to examine the reliability of the commonly used ab initio methods and hybrid density functional levels of theory in comparison with results from CCSD(T) calculations to accurately model TADA reactions. The energy barriers obtained using the M06-2X functional were found to be in quantitative agreement with the CCSD(T) level of theory using a reasonably large basis set. Conformational properties of the reactants have been systematically studied using extensive molecular dynamics (MD) simulations. For this purpose, model systems were conceived, and force field parameters corresponding to the dihedral terms in the potential energy function were obtained. Linear relationship between the activation energies corresponding to the TADA reactions and the probability of finding the reactant in certain conformational states was obtained. A clustering method along with optimizations at the molecular mechanics and density functional M06-2X levels has been used to locate the most stable conformation of each of the trienes.     

A force field for monosaccharides and (1 → 4) linked polysaccharides

A force field for monosaccharides that can be extended to (1 → 4) linked polysaccharides has been developed for the AMBER potential function. The resulting force field is consistent with the existing AMBER force field for proteins and nucleic acids. Modifications to the standard AMBER OH force constant and to the Lennard-Jones parameters were made. Furthermore, a 10–12 nonbonded term was included between the hydroxyl hydrogen of the saccharide and the water oxygen (TIP3P, SPC/E, etc.) to reproduce better the water–saccharide intermolecular distances. STO-3G electrostatic potential (ESP) charges were used to represent the electrostatic interactions between the saccharide and its surrounding environment. To obtain charges for polysaccharides, a scheme was developed to piece together saccharide residues through 1 → 4 connections while still retaining a net neutral charge on the molecule as a whole. Free energy perturbation (FEP) simulations of D -glucose and D -mannose in water were performed to test the resulting force field. The FEP simulations demonstrate that AMBER overestimates intramolecular interaction energies, suggesting that further improvements are needed in this part of the force field. To test further the reliability of the parameters, a molecular dynamics (MD) simulation of α-D -glucose in water was also performed. The MD simulation was able to produce structural and conformational results that are in accord with experimental evidence and previous theoretical results. Finally, a relaxed conformational map of β-maltose was assembled and it was found that the present force field is consistent with available theoretical and experimental results. © 1994 by John Wiley & Sons, Inc.     

Ab initio protein structure prediction with force field parameters derived from water-phase quantum chemical calculation

Molecular dynamics (MD) simulations are extensively used in the study of the structures and functions of proteins. Ab initio protein structure prediction is one of the most important subjects in computational biology, and many trials have been performed using MD simulation so far. Since the results of MD simulations largely depend on the force field, reliable force field parameters are indispensable for the success of MD simulation. In this work, we have modified atom charges in a standard force field on the basis of water-phase quantum chemical calculations. The modified force field turned out appropriate for ab initio protein structure prediction by the MD simulation with the generalized Born method. Detailed analysis was performed in terms of the conformational stability of amino acid residues, the stability of secondary structure of proteins, and the accuracy for prediction of protein tertiary structure, comparing the modified force field with a standard one. The energy balance between alpha-helix and beta-sheet structures was significantly improved by the modification of charge parameters.     

Analyzing the robustness of the MM/PBSA free energy calculation method: application to DNA conformational transitions

The ability to predict and characterize free energy differences associated with conformational equilibria or the binding of biomolecules is vital to understanding the molecular basis of many important biological functions. As biological studies focus on larger molecular complexes and properties of the genome, proteome, and interactome, the development and characterization of efficient methods for calculating free energy becomes increasingly essential. The aim of this study is to examine the robustness of the end-point free energy method termed the molecular mechanics Poisson-Boltzmann solvent accessible surface area (MM/PBSA) method. Specifically, applications of MM/PBSA to the conformational equilibria of nucleic acid (NA) systems are explored. This is achieved by comparing A to B form DNA conformational free energy differences calculated using MM/PBSA with corresponding free energy differences determined with a more rigorous and time-consuming umbrella sampling algorithm. In addition, the robustness of NA MM/PBSA calculations is also evaluated in terms of the sensitivity towards the choice of force field and the choice of solvent model used during conformational sampling. MM/PBSA calculations of the free energy difference between A-form and B-form DNA are shown to be in very close agreement with the PMF result determined using an umbrella sampling approach. Further, it is found that the MM/PBSA conformational free energy differences were also in agreement using either the CHARMM or AMBER force field. The influence of ionic strength on conformational stability was particularly insensitive to the choice of force field. Finally, it is also shown that the use of a generalized Born implicit solvent during conformational sampling results in free energy estimates that deviate slightly from those obtained using explicitly solvated MD simulations in these NA systems.     

The COMPASS force field: parameterization and validation for phosphazenes

A new, condensed-phase optimised ab-initio force field, COMPASS, has been developed recently. In this paper, the validation of COMPASS for phosphazenes is presented. The functional forms of this force field are of the consistent force field (CFF) type. Charges and bonded terms were derived from HF/6–31G1 calculations, while the nonbonded parameters (L-J 9-6 vdW potential) were initially transferred from the polymer consistent force field, pcff, and optimised using MD simulations of condensed-phase properties. As a validation of COMPASS, molecular mechanics calculations and molecular dynamics simulations have been made on a number of isolated molecules, liquids, and crystals. The calculated molecular structure, vibration frequencies, conformational properties for isolated molecules, crystal cell parameters and density, liquid density, and heat of evaporation agreed favourably with most experimental data. The special conformational properties of the tetracyclophosphazenes, (NPCI₂)₄ and (NPF₂)₄, in the solid state are discussed based on molecular mechanics and CASTEP ab-initio calculations. The effect of nonbonded cutoff distance and different algorithms for pressure control in NPT simulation was also investigated. Finally, molecular dynamics using the COMPASS force field was used to predict properties of three isomers of high-molecular-weight amorphous poly(dibutoxyphosphazenes). In this case, excellent agreement was achieved between densities and glass transition temperatures obtained from dynamics and experimental data.     

New force field for calcium binding sites in annexin-membrane complexes

For accurate classical molecular dynamics (MD) simulations of the calcium mediated bound complexes of annexin and membrane we have developed new force-field parameters correctly describing the interaction of the Ca ion with its environment. We have used quantum chemical calculations to investigate the potential energy surface experienced by the Ca ion within the three different binding sites found in domain 1 of annexin V (ANX V/1). Based on these calculations we were able to quantify the charge polarization of atoms within the binding sites, and to determine the geometry and force constants of harmonic restraints between the Ca ion and its coordinating oxygen atoms. Harmonic restraints were introduced to compensate for the deviations between the quantum mechanical potential energy surface and that of the classical force field. Our analysis has shown that using the refined force field for the Ca binding sites enables long-time MD simulations that conserve the initial structure of ANX V/1 significantly better than MD simulations using the standard force field.     

Polyunsaturated fatty acids in lipid bilayers: intrinsic and environmental contributions to their unique physical properties.

Polyunsaturated lipids are an essential component of biological membranes, influencing order and dynamics of lipids, protein-lipid interaction, and membrane transport properties. To gain an atomic level picture of the impact of polyunsaturation on membrane properties, quantum mechanical (QM) and empirical force field based calculations have been undertaken. The QM calculations of the torsional energy surface for rotation about vinyl-methylene bonds reveal low barriers to rotation, indicating an intrinsic propensity toward flexibility. Based on QM and experimental data, empirical force field parameters were developed for polyunsaturated lipids and applied in a 16 ns molecular dynamics (MD) simulation of a 1-stearoyl-2-docosahexaenoyl-sn-glyerco-3-phosphocholine (SDPC) lipid bilayer. The simulation results are in good agreement with experimental data, suggesting an unusually high degree of conformational flexibility of polyunsaturated hydrocarbon chains in membranes. The detailed analysis of chain conformation and dynamics by simulations is aiding the interpretation of experimental data and is useful for understanding the unique role of polyunsaturated lipids in biological membranes. The complete force field is included as Supporting Information and is available from http://www.pharmacy.umaryland.edu/faculty/amackere/research.html.     

O?+?C2H4 potential energy surface: lowest-lying singlet at the multireference level

Extensive density functional theory (DFT) calculations have been performed to develop a force field for the classical molecular dynamics (MD) simulations of various azobenzene derivatives. Besides azobenzene, we focused on a thiolated azobenzene’s molecular rod (4′-{[(1,1′-biphenyl)-4-yl]diazenyl}-(1,1′-biphenyl)-4-thiol) that has been previously demonstrated to photoisomerize from trans to cis with high yields on surfaces. The developed force field is an extension of OPLS All Atoms, and key bonding parameters are parameterized to reproduce the potential energy profiles calculated by DFT. For each of the parameterized molecule, we propose three sets of parameters: one best suited for the trans configuration, one for the cis configuration, and finally, a set able to describe both at a satisfactory degree. The quality of the derived parameters is evaluated by comparing with structural and vibrational experimental data. The developed force field opens the way to the classical MD simulations of self-assembled monolayers (SAMs) of azobenzene’s molecular rods, as well as to the quantum mechanics/molecular mechanics study of photoisomerization in SAMs.     

Impact of 2'-hydroxyl sampling on the conformational properties of RNA: update of the CHARMM all-atom additive force field for RNA

Here, we present an update of the CHARMM27 all-atom additive force field for nucleic acids that improves the treatment of RNA molecules. The original CHARMM27 force field parameters exhibit enhanced Watson-Crick base pair opening which is not consistent with experiment, whereas analysis of molecular dynamics (MD) simulations show the 2'-hydroxyl moiety to almost exclusively sample the O3' orientation. Quantum mechanical (QM) studies of RNA related model compounds indicate the energy minimum associated with the O3' orientation to be too favorable, consistent with the MD results. Optimization of the dihedral parameters dictating the energy of the 2'-hydroxyl proton targeting the QM data yielded several parameter sets, which sample both the base and O3' orientations of the 2'-hydroxyl to varying degrees. Selection of the final dihedral parameters was based on reproduction of hydration behavior as related to a survey of crystallographic data and better agreement with experimental NMR J-coupling values. Application of the model, designated CHARMM36, to a collection of canonical and noncanonical RNA molecules reveals overall improved agreement with a range of experimental observables as compared to CHARMM27. The results also indicate the sensitivity of the conformational heterogeneity of RNA to the orientation of the 2'-hydroxyl moiety and support a model whereby the 2'-hydroxyl can enhance the probability of conformational transitions in RNA.     

端羟基聚丁二烯/增塑剂共混物相容性的分子动力学模拟和介观模拟

应用分子动力学(MD)和介观动力学(MesoDyn)模拟方法对固体推进剂中端羟基聚丁二烯(HTPB)与增塑剂癸二酸二辛酯(DOS)、硝化甘油(NG)的相容性进行了研究. 采用MD模拟方法在COMPASS力场下, 对纯物质、HTPB/增塑剂共混物的密度、内聚能密度、溶度参数和共混物分子间的Flory-Huggins作用参数及结合能等进行了模拟计算, 通过比较溶度参数差值(Δδ)的大小、模拟前后体系密度变化情况均可以预测HTPB与增塑剂的相容性, 结合能的分析揭示了HTPB/增塑剂共混物组分间的相互作用及本质. 将Flory-Huggins作用参数转化为MesoDyn模拟的输入参数, 采用MesoDyn模拟方法对HTPB/增塑剂共混体系的介观形貌与动力学演变过程进行了研究, 通过模拟得到的等密度图、自由能密度和有序度参数等可以判断共混体系的相容性. MD和MesoDyn模拟结果均表明: HTPB/DOS属于相容体系, 而HTPB/NG属于不相容体系, 其结论与实验结果一致.     

Conformational analysis of six- and twelve-membered ring compounds by molecular dynamics

A molecular dynamics (MD)-based conformational analysis has been performed on a number of cycloalkanes in order to demonstrate the reliability and generality of MD as a tool for conformational analysis. MD simulations on cyclohexane and a series of methyl-substituted cyclohexanes were performed at temperatures between 400 and 1200 K. Depending on the simulation temperature, different types of interconversions (twist-boat–twist-boat, twist- boat–chair and chair–chair) could be observed, and the MD simulations demonstrated the expected correlation between simulation temperature and ring inversion barriers. A series of methyl-substituted 1,3- dioxanes were investigated at 1000 K, and the number of chair–chair interconversions could be quantitatively correlated to the experimentally determined ring inversion barrier. Similarly, the distribution of sampled minimum-energy conformations correlated with the energy-derived Boltzmann distribution. The macrocyclic ring system cyclododecane was subjected to an MD simulation at 1000 K and 71 different conformations could be sampled. These conformations were compared with the results of previously reported conformational analyses using stochastic search methods, and the MD method provided 19 out of the 20 most stable conformations found in the MM2 force field. Finally, the general performance of the MD method for conformational analysis is discussed.     

Force-field development and molecular dynamics simulations of ferrocene-peptide conjugates as a scaffold for hydrogenase mimics

The increasing importance of hydrogenase enzymes in the new energy research field has led us to examine the structure and dynamics of potential hydrogenase mimics, based on a ferrocene-peptide scaffold, using molecular dynamics (MD) simulations. To enable this MD study, a molecular mechanics force field for ferrocene-bearing peptides was developed and implemented in the CHARMM simulation package, thus extending the usefulness of the package into peptide-bioorganometallic chemistry. Using the automated frequency-matching method (AFMM), optimized intramolecular force-field parameters were generated through quantum chemical reference normal modes. The partial charges for ferrocene were derived by fitting point charges to quantum-chemically computed electrostatic potentials. The force field was tested against experimental X-ray crystal structures of dipeptide derivatives of ferrocene-1,1'-dicarboxylic acid. The calculations reproduce accurately the molecular geometries, including the characteristic C2-symmetrical intramolecular hydrogen-bonding pattern, that were stable over 0.1 micros MD simulations. The crystal packing properties of ferrocene-1-(D)alanine-(D)proline-1'-(D)alanine-(D)proline were also accurately reproduced. The lattice parameters of this crystal were conserved during a 0.1 micros MD simulation and match the experimental values almost exactly. Simulations of the peptides in dichloromethane are also in good agreement with experimental NMR and circular dichroism (CD) data in solution. The developed force field was used to perform MD simulations on novel, as yet unsynthesized peptide fragments that surround the active site of [Ni-Fe] hydrogenase. The results of this simulation lead us to propose an improved design for synthetic peptide-based hydrogenase models. The presented MD simulation results of metallocenes thereby provide a convincing validation of our proposal to use ferrocene-peptides as minimal enzyme mimics.     

Parametrization, molecular dynamics simulation, and calculation of electron spin resonance spectra of a nitroxide spin label on a polyalanine alpha-helix

The nitroxide spin label 1-oxyl-2,2,5,5-tetramethylpyrroline-3-methyl-methanethiosulfonate (MTSSL), commonly used in site-directed spin labeling of proteins, is studied with molecular dynamics (MD) simulations. After developing force field parameters for the nitroxide moiety and the spin label linker, we simulate MTSSL attached to a polyalanine alpha-helix in explicit solvent to elucidate the factors affecting its conformational dynamics. Electron spin resonance spectra at 9 and 250 GHz are simulated in the time domain using the MD trajectories and including global rotational diffusion appropriate for the tumbling of T4 Lysozyme in solution. Analysis of the MD simulations reveals the presence of significant hydrophobic interactions of the spin label with the alanine side chains.     

Application of torsion angle molecular dynamics for efficient sampling of protein conformations

We investigate the application of torsion angle molecular dynamics (TAMD) to augment conformational sampling of peptides and proteins. Interesting conformational changes in proteins mainly involve torsional degrees of freedom. Carrying out molecular dynamics in torsion space does not only explicitly sample the most relevant degrees of freedom, but also allows larger integration time steps with elimination of the bond and angle degrees of freedom. However, the covalent geometry needs to be fixed during internal coordinate dynamics, which can introduce severe distortions to the underlying potential surface in the extensively parameterized modern Cartesian-based protein force fields. A "projection" approach (Katritch et al. J Comput Chem 2003, 24, 254-265) is extended to construct an accurate internal coordinate force field (ICFF) from a source Cartesian force field. Torsion crossterm corrections constructed from local molecular fragments, together with softened van der Waals and electrostatic interactions, are used to recover the potential surface and incorporate implicit bond and angle flexibility. MD simulations of dipeptide models demonstrate that full flexibility in both the backbone phi/psi and side chain chi1 angles are virtually restored. The efficacy of TAMD in enhancing conformational sampling is then further examined by folding simulations of small peptides and refinement experiments of protein NMR structures. The results show that an increase of several fold in conformational sampling efficiency can be reliably achieved. The current study also reveals some complicated intrinsic properties of internal coordinate dynamics, beyond energy conservation, that can limit the maximum size of the integration time step and thus the achievable gain in sampling efficiency.     

端羟基聚丁二烯/增塑剂共混物相容性的分子动力学模拟

固体推进剂和炸药的力学性能在很大程度上依赖于配方中高分子粘结剂与增塑剂的相容性. 本文对相容和非相容两种体系进行了分子动力学(MD)模拟, 以考察分子模拟方法的实用性. 为预测固体推进剂中端羟基聚丁二烯(HTPB)与增塑剂癸二酸二辛酯(DOS)、硝化甘油(NG)的相容性, 采用MD模拟方法在COMPASS力场下, 对HTPB、DOS、NG和共混物HTPB/DOS、HTPB/NG的密度、内聚能密度及溶度参数等进行了模拟计算. 通过比较溶度参数差值(△δ)的大小、分子间径向分布函数和模拟前后体系密度变化情况均可以预测HTPB/DOS属于相容体系,而HTPB/NG属于不相容体系, 与实验结果一致. 径向分布函数分析同时揭示了HTPB/增塑剂组分之间的相互作用及本质. 本文的模拟方法可以作为预测聚合物与增塑剂相容性的有利工具, 也可以为固体推进剂和炸药的配方设计提供理论指导.     

Estimating kinetic rates from accelerated molecular dynamics simulations: alanine dipeptide in explicit solvent as a case study

Molecular dynamics (MD) simulation is the standard computational technique used to obtain information on the time evolution of the conformations of proteins and many other molecular systems. However, for most biological systems of interest, the time scale for slow conformational transitions is still inaccessible to standard MD simulations. Several sampling methods have been proposed to address this issue, including the accelerated molecular dynamics method. In this work, we study the extent of sampling of the phi/psi space of alanine dipeptide in explicit water using accelerated molecular dynamics and present a framework to recover the correct kinetic rate constant for the helix to beta-strand transition. We show that the accelerated MD can drastically enhance the sampling of the phi/psi conformational phase space when compared to normal MD. In addition, the free energy density plots of the phi/psi space show that all minima regions are accurately sampled and the canonical distribution is recovered. Moreover, the kinetic rate constant for the helix to beta-strand transition is accurately estimated from these simulations by relating the diffusion coefficient to the local energetic roughness of the energy landscape. Surprisingly, even for such a low barrier transition, it is difficult to obtain enough transitions to accurately estimate the rate constant when one uses normal MD.     

Conformational dynamics in nitrogen-fused azabicycles

Using molecular mechanics (MM3 force field)-based methodology, conformational dynamics have been studied for 1-azabicyclo[2.2.0]hexane, 1-azabicylo[3.3.0]octane, and 1-azabicylo[4.4.0]decane. Obtained conformational schemes describe the flexibity of these parent azabicyles as well as permit us to estimate conformational mobility in related N-fused systems. Quantum mechanics ab initio calculations have been used in order to check the reliability of molecular mechanics-provided estimates of relative energy of conformers. The previous dynamic NMR (DNMR) data have been reinterpreted for some polycyclic alkaloids.     

Investigation of ligand exchange reactions in aqueous uranyl carbonate complexes using computational approaches

Carbonate anion exchange reactions with water in the uranyl-carbonate and calcium-uranyl-carbonate aqueous systems have been investigated using computational methods. Classical molecular dynamics (MD) simulations with the umbrella sampling technique were employed to determine potentials of mean force for the exchange reactions of water and carbonate. The presence of calcium counter-ions is predicted to increase the stability of the uranyl-carbonate species in accordance with previous experimental observations. However, the free energy barrier to carbonate exchange with water is found to be comparable both in the presence and absence of calcium cations. Possible implications of these results for uranyl adsorption on mineral surfaces are discussed. Density functional theory (DFT) calculations were also used to confirm the trends observed in classical molecular dynamics simulations and to corroborate the validity of the potential parameters employed in the MD scheme.     

Optimization and application of lithium parameters for the reactive force field, ReaxFF

To make a practical molecular dynamics (MD) simulation of the large-scale reactive chemical systems of Li-H and Li-C, we have optimized parameters of the reactive force field (ReaxFF) for these systems. The parameters for this force field were obtained from fitting to the results of density functional theory (DFT) calculations on the structures and energy barriers for a number of Li-H and Li-C molecules, including Li(2), LiH, Li(2)H(2), H(3)C-Li, H(3)C-H(2)C-Li, H(2)C=C-LiH, HCCLi, H(6)C(5)-Li, and Li(2)C(2), and to the equations of state and lattice parameters for condensed phases of Li. The accuracy of the developed ReaxFF was also tested by comparison to the dissociation energies of lithium-benzene sandwich compounds and the collision behavior of lithium atoms with a C(60) buckyball.