Novel organomagnesium reagents in synthesis. Catalytic cyclomagnesiation of allenes in the synthesis of N-, O-, and Si-substituted 1Z,5Z-dienes

An efficient method for the synthesis of valuable N-, O-, and Si-containing 1Z,5Z-diene compounds was developed. The method comprises Cp₂TiCl₂-catalyzed homo- and cross-cyclomagnesiation of 1,2-dienes by Grignard reagents (RMgR′) to give 2,5-dialkylidenemagnesacyclopentanes in up to 96% yield. This approach was successfully used in the synthesis of 5Z,9Z-dienoic acids, precursors of acetogenins and insect pheromones.     

Synthesis of trisubstituted thiazoles by ligand-free palladium-catalyzed direct 5-arylation of 2,4-disubstituted thiazoles under conventional and microwave-assisted heating

Trisubstituted thiazoles were synthesized with excellent yields using ligand-free, palladium-catalyzed, direct 5-arylation of 2,4-disubstituted thiazole and conventional or microwave-assisted heating. The palladium-catalyzed reaction yields were significantly influenced by LiCl additive, solvent, and heating method. The reaction times were reduced dramatically by employing microwave radiation instead of conventional heating. The synthetic methods can be applied to diverse 2,4,5-trisubstituted thiazoles by varying the aryl bromide and disubstituted thiazole reactants.     

Domino reactions in water for the stereoselective synthesis of novel spiro dihydro-2′H-[indene-2,3′-thiophen]-1(3H)-ones with three contiguous stereocenters

The domino reactions of (E)-2-(aryl)-2,3-dihydro-1H-inden-1-ones and 1,4-dithiane-2,5-diol in the presence of triethylamine in water stereoselectively afforded a library of 2′-(aryl)-4′-hydroxy-4′,5′-dihydro-2′H-spiro[indene-2,3′-thiophen]-1(3H)-ones. This transformation presumably proceeds via the generation of 2-mercaptoacetaldehyde from 1,4-dithiane-2,5-diol followed by Michael addition–intramolecular aldol sequence with C–C and C–S bond formations and creation of three contiguous stereocenters in a one-pot operation.     

FIPSDock: A new molecular docking technique driven by fully informed swarm optimization algorithm

The accurate prediction of protein–ligand binding is of great importance for rational drug design. We present herein a novel docking algorithm called as FIPSDock, which implements a variant of the Fully Informed Particle Swarm (FIPS) optimization method and adopts the newly developed energy function of AutoDock 4.20 suite for solving flexible protein–ligand docking problems. The search ability and docking accuracy of FIPSDock were first evaluated by multiple cognate docking experiments. In a benchmarking test for 77 protein/ligand complex structures derived from GOLD benchmark set, FIPSDock has obtained a successful predicting rate of 93.5% and outperformed a few docking programs including particle swarm optimization (PSO)@AutoDock, SODOCK, AutoDock, DOCK, Glide, GOLD, FlexX, Surflex, and MolDock. More importantly, FIPSDock was evaluated against PSO@AutoDock, SODOCK, and AutoDock 4.20 suite by cross‐docking experiments of 74 protein–ligand complexes among eight protein targets (CDK2, ESR1, F2, MAPK14, MMP8, MMP13, PDE4B, and PDE5A) derived from Sutherland‐crossdock‐set. Remarkably, FIPSDock is superior to PSO@AutoDock, SODOCK, and AutoDock in seven out of eight cross‐docking experiments. The results reveal that FIPS algorithm might be more suitable than the conventional genetic algorithm‐based algorithms in dealing with highly flexible docking problems. © 2012 Wiley Periodicals, Inc.     

DOT2: Macromolecular docking with improved biophysical models

Computational docking is a useful tool for predicting macromolecular complexes, which are often difficult to determine experimentally. Here, we present the DOT2 software suite, an updated version of the DOT intermolecular docking program. DOT2 provides straightforward, automated construction of improved biophysical models based on molecular coordinates, offering checkpoints that guide the user to include critical features. DOT has been updated to run more quickly, allow flexibility in grid size and spacing, and generate an infinitive complete list of favorable candidate configurations. Output can be filtered by experimental data and rescored by the sum of electrostatic and atomic desolvation energies. We show that this rescoring method improves the ranking of correct complexes for a wide range of macromolecular interactions and demonstrate that biologically relevant models are essential for biologically relevant results. The flexibility and versatility of DOT2 accommodate realistic models of complex biological systems, improving the likelihood of a successful docking outcome. © 2013 Wiley Periodicals, Inc.     

High–quality protein backbone reconstruction from alpha carbons using Gaussian mixture models

Coarse‐grained protein structure models offer increased efficiency in structural modeling, but these must be coupled with fast and accurate methods to revert to a full‐atom structure. Here, we present a novel algorithm to reconstruct mainchain models from C traces. This has been parameterized by fitting Gaussian mixture models (GMMs) to short backbone fragments centered on idealized peptide bonds. The method we have developed is statistically significantly more accurate than several competing methods, both in terms of RMSD values and dihedral angle differences. The method produced Ramachandran dihedral angle distributions that are closer to that observed in real proteins and better Phaser molecular replacement log‐likelihood gains. Amino acid residue sidechain reconstruction accuracy using SCWRL4 was found to be statistically significantly correlated to backbone reconstruction accuracy. Finally, the PD2 method was found to produce significantly lower energy full‐atom models using Rosetta which has implications for multiscale protein modeling using coarse‐grained models. A webserver and C++ source code is freely available for noncommercial use from: http://www.sbg.bio.ic.ac.uk/phyre2/PD2_ca2main/ . © 2013 Wiley Periodicals, Inc.     

CHARMM36 all‐atom additive protein force field: Validation based on comparison to NMR data

Protein structure and dynamics can be characterized on the atomistic level with both nuclear magnetic resonance (NMR) experiments and molecular dynamics (MD) simulations. Here, we quantify the ability of the recently presented CHARMM36 (C36) force field (FF) to reproduce various NMR observables using MD simulations. The studied NMR properties include backbone scalar couplings across hydrogen bonds, residual dipolar couplings (RDCs) and relaxation order parameter, as well as scalar couplings, RDCs, and order parameters for side‐chain amino‐ and methyl‐containing groups. It is shown that the C36 FF leads to better correlation with experimental data compared to the CHARMM22/CMAP FF and suggest using C36 in protein simulations. Although both CHARMM FFs contains the same nonbond parameters, our results show how the changes in the internal parameters associated with the peptide backbone via CMAP and the χ₁ and χ₂ dihedral parameters leads to improved treatment of the analyzed nonbond interactions. This highlights the importance of proper treatment of the internal covalent components in modeling nonbond interactions with molecular mechanics FFs. © 2013 Wiley Periodicals, Inc.     

Computational gibberellin‐binding channel discovery unraveling the unexpected perception mechanism of hormone signal by gibberellin receptor

Gibberellins (GAs) are phytohormones essential for many developmental processes in plants. In this work, fundamental mechanism of hormone perception by receptor GID1 has been studied by performing computational simulations, revealing a new GA‐binding channel of GID1 and a novel hormone perception mechanism involving only one conformational state of GID1. The novel hormone perception mechanism demonstrated here is remarkably different from the previously proposed/speculated mechanism [Murase et al., Nature 2008 , 456, 459] involving two conformational states (“OPEN” and “CLOSED”) of GID1. According to the new perception mechanism, GA acts as a “conformational stabilizer,” rather than the previously speculated “allosteric inducer,” to induce the recognition of protein DELLA by GID1. The novel mechanistic insights obtained in this study provide a new starting point for further studies on the detailed molecular mechanisms of GID1 interacting with DELLA and various hormones and for mechanism‐based rational design of novel, potent growth regulators that target crops and ornamental plants. © 2013 Wiley Periodicals, Inc.     

Rotamer decomposition and protein dynamics: Efficiently analyzing dihedral populations from molecular dynamics

Molecular mechanics methods have matured into powerful methods to understand the dynamics and flexibility of macromolecules and especially proteins. As multinanosecond to microsecond length molecular dynamics (MD) simulations become commonplace, advanced analysis tools are required to generate scientifically useful information from large amounts of data. Some of the key degrees of freedom to understand protein flexibility and dynamics are the amino acid residue side chain dihedral angles. In this work, we present an easily automated way to summarize and understand the relevant dihedral populations. A tremendous reduction in complexity is achieved by describing dihedral timeseries in terms of histograms decomposed into Gaussians. Using the familiar and widely studied protein lysozyme, it is demonstrated that our approach captures essential properties of protein structure and dynamics. A simple classification scheme is proposed that indicates the rotational state population for each dihedral angle of interest and allows a decision if a given side chain or peptide backbone fragment remains rigid during the course of an MD simulation, adopts a converged distribution between conformational substates or has not reached convergence yet. © 2012 Wiley Periodicals, Inc.     

Two‐dimensional replica‐exchange method for predicting protein–ligand binding structures

We have developed a two‐dimensional replica‐exchange method for the prediction of protein–ligand binding structures. The first dimension is the umbrella sampling along the reaction coordinate, which is the distance between a protein binding pocket and a ligand. The second dimension is the solute tempering, in which the interaction between a ligand and a protein and water is weakened. The second dimension is introduced to make a ligand follow the umbrella potential more easily and enhance the binding events, which should improve the sampling efficiency. As test cases, we applied our method to two protein‐ligand complex systems (MDM2 and HSP 90‐alpha). Starting from the configuration in which the protein and the ligand are far away from each other in each system, our method predicted the ligand binding structures in excellent agreement with the experimental data from Protein Data Bank much faster with the improved sampling efficiency than the replica‐exchange umbrella sampling method that we have previously developed. © 2013 Wiley Periodicals, Inc.