Ab initio study on stacking sequences, free energy, dynamical stability and potential energy surfaces of graphite structures

Reaching the native states of small proteins, a necessary step towards a comprehensive understanding of the folding mechanisms, has remained a tremendous challenge to ab initio protein folding simulations despite the extensive effort. In this work, the folding process of the B domain of protein A (BdpA) has been simulated by both conventional and replica exchange molecular dynamics using AMBER FF03 all-atom force field. Started from an extended chain, a total of 40 conventional (each to 1.0 micros) and two sets of replica exchange (each to 200.0 ns per replica) molecular dynamics simulations were performed with different generalized-Born solvation models and temperature control schemes. The improvements in both the force field and solvent model allowed successful simulations of the folding process to the native state as demonstrated by the 0.80 A C(alpha) root mean square deviation (RMSD) of the best folded structure. The most populated conformation was the native folded structure with a high population. This was a significant improvement over the 2.8 A C(alpha) RMSD of the best nativelike structures from previous ab initio folding studies on BdpA. To the best of our knowledge, our results demonstrate, for the first time, that ab initio simulations can reach the native state of BdpA. Consistent with experimental observations, including Phi-value analyses, formation of helix II/III hairpin was a crucial step that provides a template upon which helix I could form and the folding process could complete. Early formation of helix III was observed which is consistent with the experimental results of higher residual helical content of isolated helix III among the three helices. The calculated temperature-dependent profile and the melting temperature were in close agreement with the experimental results. The simulations further revealed that phenylalanine 31 may play critical to achieve the correct packing of the three helices which is consistent with the experimental observation. In addition to the mechanistic studies, an ab initio structure prediction was also conducted based on both the physical energy and a statistical potential. Based on the lowest physical energy, the predicted structure was 2.0 A C(alpha) RMSD away from the experimentally determined structure.

We investigate temperature dependency of the activation free energy for the atomic diffusion in the fcc Lennrad-Jones system within the transition states theory based on the quasi-harmonic approximation. The activation free energy consists of the static activation energy and the vibrational free energy difference between the saddle point and the equilibrium state, and it is shown that both of them strongly depend on the system volume and the temperature. The temperature dependencies of both quantities exhibit opposite tendencies, i.e., the static activation energy decreases, while the free energy difference increases with increasing temperature. As a result, the activation free energy shows a weak temperature dependency. We discuss the effects of anharmonicity on the activation free energy by comparing the activation free energy obtained by the quasi-harmonic and harmonic approximations.

Many biomolecules undergo conformational changes associated with allostery or ligand binding. Observing these changes in computer simulations is difficult if their timescales are long. These calculations can be accelerated by observing the transition on an auxiliary free energy surface with a simpler Hamiltonian and connecting this free energy surface to the target free energy surface with free energy calculations. Here, we show that the free energy legs of the cycle can be replaced with energy representation (ER) density functional approximations. We compute: (1) The conformational free energy changes for alanine dipeptide transitioning from the right-handed free energy basin to the left-handed basin and (2) the free energy difference between the open and closed conformations of β-cyclodextrin, a "host" molecule that serves as a model for molecular recognition in host-guest binding. β-cyclodextrin contains 147 atoms compared to 22 atoms for alanine dipeptide, making β-cyclodextrin a large molecule for which to compute solvation free energies by free energy perturbation or integration methods and the largest system for which the ER method has been compared to exact free energy methods. The ER method replaced the 28 simulations to compute each coupling free energy with two endpoint simulations, reducing the computational time for the alanine dipeptide calculation by about 70% and for the β-cyclodextrin by > 95%. The method works even when the distribution of conformations on the auxiliary free energy surface differs substantially from that on the target free energy surface, although some degree of overlap between the two surfaces is required. © 2016 Wiley Periodicals, Inc.

The conformational analysis of the HIV-1 reverse transcriptase inhibitor, (+)-(s)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazol[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione or 9-Cl TIBO, has been investigated using high level of calculations, ab initio, and DFT theory. The potential energy surface as the function of two important rotatable dihedral angles of the 9-Cl TIBO side chain was generated by the Hartree−Fock method at the 3-21G basis set. Eight pronounced local minima were found to exist within an energy difference of less than 10 kJ/mol. The energy barriers between the different local minima are lower than 15 kJ/mol. A second derivative (frequency) analysis showed that all conformers are stable at this level of theory. These structures were used as starting points for full geometry optimizations at the HF/6-31G** and B3LYP/6-31G** levels of theory to obtain the absolute geometries and structural information. The comparisons of calculated conformers with the bound conformer in th...

The conformation of dimethyl (R,R)-tartrate has been analyzed on the basis of the single crystal X-ray diffraction method as well as by ab-initio quantum chemical studies. The results showed that the extended T conformation containing two planar hydroxyester moieties predominates in both ab-initio and X-ray studies. The lowest energy conformer in ab-initio calculations has C2 symmetry and hydrogen bonds between a hydroxyl group and the nearest carbonyl oxygen. The second in energetical sequence, with an energy difference of only 1.2 kcal/mol, is the asymmetrical conformer, which differs from the lowest energy form by the rotation of one of the ester groups by 180°. Intramolecular OH...O hydrogen bonds observed in this rotamer again involve only proximal functional groups. This conformer is present in the crystal structure of the studied compound, although its conformation in the solid state is no longer stabilized by intramolecular hydrogen bonds of the type mentioned above. In the crystal, hydroxyl groups are mostly involved in intermolecular hydrogen bonds and form only a weak intramolecular hydrogen bond with each other. The planar arrangement of the α-hydroxyester moieties combined with the extended conformation of the carbon chain seems to be stabilized by the intramolecular hydrogen bonds between neighboring functional groups and by the long range dipole-dipole interactions between two pairs of CO and (β)C-H bonds.

We report an ab initio molecular dynamics simulation study of a complex composed of the superoxide anion and four water molecules. We probe the symmetry and stability of the superoxide tetrahydrate anion cluster at a low temperature (25 K) where there are vibrational spectra and a higher temperature (111 K) where experimental data are not available. From the ab initio simulation trajectory, we found the superoxide tetrahydrate complex to be highly symmetric, exhibiting a collective breathing motion on the picosecond time scale at low temperature that subsequently disappears at higher temperatures. Furthermore, we establish that superoxide tetrahydrate is a highly stable species at the higher temperature with little or no distortion to its geometry. The vibrational spectrum calculated from our ab initio trajectory is in reasonable agreement with experimental spectra, and we were able to assign individual peaks in the spectra to specific modes in the superoxide tetrahydrate anion cluster.

We describe a flexible and broadly applicable energy refinement method, "nebterpolation," for identifying and characterizing the reaction events in a molecular dynamics (MD) simulation. The new method is applicable to ab initio simulations with hundreds of atoms containing complex and multimolecular reaction events. A key aspect of nebterpolation is smoothing of the reactive MD trajectory in internal coordinates to initiate the search for the reaction path on the potential energy surface. We apply nebterpolation to analyze the reaction events in an ab initio nanoreactor simulation that discovers new molecules and mechanisms, including a C-C coupling pathway for glycolaldehyde synthesis. We find that the new method, which incorporates information from the MD trajectory that connects reactants with products, produces a dramatically distinct set of minimum energy paths compared to existing approaches that start from information for the reaction end points alone. The energy refinement method described here represents a key component of an emerging simulation paradigm where molecular dynamics simulations are applied to discover the possible reaction mechanisms.

ES/IS: Estimation of conformational free energy by combining dynamics simulations with explicit solvent with an implicit solvent continuum model

A new six-dimensional analytical potential energy surface for the hydrogen bonded dimer (HF)2 is presented. It is based on the ab initio study by Kofranek et al., and uses 1070 points with energies up to 500 kJ mol-1 as well as recent correlated dispersion coefficients from a perturbation treatment by Rijks and Wormer, and the experimental Morse parameters for the HF monomer. The fit to the ab initio points contains 29 free and several constrained parameters and has a weighted standard deviation of 29·5 cm-1. A brief description of some properties of the new surface is given. Preliminary results of a diffusion quantum Monte Carlo (QMC) study for vibrational energy levels on the new surface as well as on a surface published by Bunker et al. are given. An interesting anharmonic isotope effect in the v 6 fundamental is discussed and explained.

Metadynamics (MTD) is a very powerful technique to sample high-dimensional free energy landscapes, and due to its self-guiding property, the method has been successful in studying complex reactions and conformational changes. MTD sampling is based on filling the free energy basins by biasing potentials and thus for cases with flat, broad, and unbound free energy wells, the computational time to sample them becomes very large. To alleviate this problem, we combine the standard Umbrella Sampling (US) technique with MTD to sample orthogonal collective variables (CVs) in a simultaneous way. Within this scheme, we construct the equilibrium distribution of CVs from biased distributions obtained from independent MTD simulations with umbrella potentials. Reweighting is carried out by a procedure that combines US reweighting and Tiwary-Parrinello MTD reweighting within the Weighted Histogram Analysis Method (WHAM). The approach is ideal for a controlled sampling of a CV in a MTD simulation, making it computationally efficient in sampling flat, broad, and unbound free energy surfaces. This technique also allows for a distributed sampling of a high-dimensional free energy surface, further increasing the computational efficiency in sampling. We demonstrate the application of this technique in sampling high-dimensional surface for various chemical reactions using ab initio and QM/MM hybrid molecular dynamics simulations. Further, to carry out MTD bias reweighting for computing forward reaction barriers in ab initio or QM/MM simulations, we propose a computationally affordable approach that does not require recrossing trajectories. © 2016 Wiley Periodicals, Inc.

Ab initio studies on carbenes; singlet and triplet conformers and vibrational spectra of hydroxy-, dihydroxy- and methylhydroxy-carbene

The recent development of ab initio simulation techniques enables us to carry out reliable simulations for liquid-state materials. As an example, we describe the results of ab initio molecular-dynamics simulations for liquid alkali-chalcogen mixtures and molten noble-metal halides. It is shown that the calculated structure factors are in good agreement with those obtained by neutron scattering experiments. We discuss the relationship between ab initio studies on liquids and neutron experiments from the viewpoint of theoretical research.

A global adiabatic potential energy surface (PES) corresponding to the second singlet state 1 1A" (1 1B1) of CH2 has been computed in a similar way as the first singlet state 1 1A' in our previous work [B. Bussery-Honvault et al., J. Chem. Phys., 2001, 115, 10 701]. This PES has a calculated well depth of 79.9 kcal mol(-1) relative to the C(1D) + H2 asymptote and correlates to CH(2pi) + H. It presents large barriers in the C(1D) + H2 arrangement for both collinear and perpendicular geometries but no barrier for geometries about 60 degrees and leads to a sideways insertion mechanism for the reaction C(1D) + H2 --> CH(2pi) + H. The ab initio calculations were carried out for 4644 geometries and the resulting energies were fitted to a many-body expansion. Accurate three-dimensional quantum mechanical scattering calculations have been performed for the C(1D) + H2(v = 0, j = 0) reaction on this ab initio 1 1A" PES in the collision energy range [0-11.5 kcal mol(-1)]. The J = 0 reaction probabilities show dense resonance structures as those obtained with the 1 1A' PES. However some different dynamical features have been found.

Quantum mechanics/molecular mechanics (QM/MM) simulations are crucial for understanding enzymatic reactions, but their accuracy depends heavily on the quantum-mechanical method used. Semiempirical methods offer computational efficiency but often struggle with accuracy in complex systems. This work presents a novel multiobjective evolutionary strategy for optimizing semiempirical Hamiltonians, specifically designed to enhance their performance in enzymatic QM/MM simulations while remaining broadly applicable to condensed-phase systems. Our methodology combines automated parameter optimization, targeting ab initio or density functional theory (DFT)-reference potential energy surfaces, atomic charges, and gradients, with comprehensive validation through minimum free energy path (MFEP) calculations. To demonstrate its effectiveness, we applied our approach to improve the GFN2-xTB Hamiltonian using two enzymatic systems that involve hydride transfer reactions where the activation energy barrier is severely underestimated: Crotonyl-CoA carboxylase/reductase (CCR) and dihydrofolate reductase (DHFR). The optimized parameters showed significant improvements in reproducing potential and free energy surfaces, closely matching higher-level DFT calculations. Through an efficient two-stage optimization process, we first developed parameters for CCR using reaction path data, then refined these parameters for DHFR by incorporating a targeted set of additional training geometries. This strategic approach minimized the computational cost while achieving accurate descriptions of both systems, as validated through QM/MM simulations using the Adaptive String Method (ASM). Our method represents an efficient approach for optimizing semiempirical methods to study larger systems and longer time scales, with potential applications in enzymatic reaction mechanism studies, drug design, and enzyme engineering.

Comparison of solvent models for characterizing stationary phase selectivity in gas chromatography