Parallel cascade selection molecular dynamics to screen for protein complexes generated by rigid docking.

We propose a flexible docking simulation based on parallel cascade selection molecular dynamics (PaCS-MD) as a post-processing treatment after a rigid docking simulation. PaCS-MD has been proposed as an enhanced sampling method for generating structural transition pathways from a given reactant to a product. The PaCS-MD cycle consists of the following two steps: (1) selections of important initial structures and (2) their conformational resampling from the selected initial structures. By repeating the conformational resampling from the important initial structures, structural transitions from the reactant to the product are gradually promoted. In the present flexible docking simulation, decoys (protein complexes) are generated by the rigid docking simulation a priori and employed as products of PaCS-MD. Then PaCS-MD is applied to reproduce association processes to the decoys from a reactant (completely separated proteins). To judge whether PaCS-MD found the association processes or not, the root-mean-square deviation measured from decoy (RMSDdecoy) was defined and monitored during the PaCS-MD cycles. By checking the RMSDdecoy values, a set of decoys is screened as a non-near native protein complex. In more detail, PaCS-MD detects near native protein complexes from the generated decoys by imposing a threshold (cutoff) for RMSDdecoy, i.e. RMSDdecoy < cutoff. As a demonstration, the present flexible docking addressed dimerization processes of K48-linked ubiquitin dimer without a covalent bond between its monomers. Finally, PaCS-MD screened out non-near native protein complexes from decoys generated by a rigid docking simulation.

Temperature-pressure shuffling outlier flooding method enhances the conformational sampling of proteins.

Outlier flooding method (OFLOOD) is an efficient conformational sampling method developed by the authors. In the present study, to further enhance the conformational sampling efficiency, a set of parameters (temperatures and pressures) specified as inputs in the original OFLOOD were shuffled before restarting the short-time molecular dynamics (MD) simulations. Because of the diversity of these parameters, it was confirmed that the extended OFLOOD becomes superior to the original one in finding the folding pathways of Trp-cage. © 2019 Wiley Periodicals, Inc.

Quantum chemical approach for positron annihilation spectra of atoms and molecules beyond plane-wave approximation.

We report theoretical calculations of positron-electron annihilation spectra of noble gas atoms and small molecules using the nuclear orbital plus molecular orbital method. Instead of a nuclear wavefunction, the positronic wavefunction is obtained as the solution of the coupled Hartree-Fock or Kohn-Sham equation for a positron and the electrons. The molecular field is included in the positronic Fock operator, which allows an appropriate treatment of the positron-molecule repulsion. The present treatment succeeds in reproducing the Doppler shift, i.e., full width at half maximum (FWHM) of experimentally measured annihilation (γ-ray) spectra for molecules with a mean absolute error less than 10%. The numerical results indicate that the interpretation of the FWHM in terms of a specific molecular orbital is not appropriate.

Rapid QM/MM approach for biomolecular systems under periodic boundary conditions: Combination of the density-functional tight-binding theory and particle mesh Ewald method.

A quantum mechanical/molecular mechanical (QM/MM) approach based on the density-functional tight-binding (DFTB) theory is a useful tool for analyzing chemical reaction systems in detail. In this study, an efficient QM/MM method is developed by the combination of the DFTB/MM and particle mesh Ewald (PME) methods. Because the Fock matrix, which is required in the DFTB calculation, is analytically obtained by the PME method, the Coulomb energy is accurately and rapidly computed. For assessing the performance of this method, DFTB/MM calculations and molecular dynamics simulation are conducted for a system consisting of two amyloid-ß(1-16) peptides and a zinc ion in explicit water under periodic boundary conditions. As compared with that of the conventional Ewald summation method, the computational cost of the Coulomb energy by utilizing the present approach is drastically reduced, i.e., 166.5 times faster. Furthermore, the deviation of the electronic energy is less than 10-6 Eh. © 2016 Wiley Periodicals, Inc.

Three pillars for achieving quantum mechanical molecular dynamics simulations of huge systems: Divide-and-conquer, density-functional tight-binding, and massively parallel computation.

The linear-scaling divide-and-conquer (DC) quantum chemical methodology is applied to the density-functional tight-binding (DFTB) theory to develop a massively parallel program that achieves on-the-fly molecular reaction dynamics simulations of huge systems from scratch. The functions to perform large scale geometry optimization and molecular dynamics with DC-DFTB potential energy surface are implemented to the program called DC-DFTB-K. A novel interpolation-based algorithm is developed for parallelizing the determination of the Fermi level in the DC method. The performance of the DC-DFTB-K program is assessed using a laboratory computer and the K computer. Numerical tests show the high efficiency of the DC-DFTB-K program, a single-point energy gradient calculation of a one-million-atom system is completed within 60 s using 7290 nodes of the K computer. © 2016 Wiley Periodicals, Inc.

Rigorous non-Born-Oppenheimer theory: combination of explicitly correlated Gaussian method and nuclear orbital plus molecular orbital theory.

The present study proposes a rigorous non-Born-Oppenheimer theory combining between the explicitly correlated Gaussian (ECG) method and the nuclear orbital plus molecular orbital (NOMO) method. The new method, called ECG-NOMO, adopts the ECG functions between the electronic and nuclear coordinates and, therefore, is capable of describing the nucleus-electron correlation effect accurately. The basic formalism of the ECG-NOMO method is close to the NOMO method, which starts with the Hartree-Fock type equations for NOs and MOs. The present method requires more computational cost than the original NOMO method. However, its cost is significantly smaller than that of the ECG method. The numerical tests was performed for hydrogen-like atoms (H-Ne(9+)) and dihydrogen cations (H(2)(+), D(2)(+) and T(2)(+)), and clarified that the ECG-NOMO method shows the sufficient accuracy.

Total synthesis of three naturally occurring 6,8-di-C-glycosylflavonoids: phloretin, naringenin, and apigenin bis-C-beta-D-glucosides.

Three naturally occurring di-C-glycosylflavonoids, phloretin (dihydrochalcone), naringenin (flavanone), and apigenin (flavone) bis-6,8-C-beta-D-glucopyranosides (4, 5, and 6), were synthesized in total yields of 52.3%, 53.5%, and 36.4%, respectively, starting from the key compound, di-C-beta-D-glucopyranosylphloroacetophenone (1). Benzyl protection of the phenolic hydroxyls in 1 and a subsequent aldol condensation with benzyloxybenzaldehyde led to the production of chalcone 3, which, after hydrogenolysis or acid hydrolysis and deprotection, gave 4 and 5, respectively. The acetylation of 5, followed by DDQ oxidation and deprotection, gave 6.