Conformational Search Method Research Articles

Molecular Dynamics‐Based Conformational Simulation Method for Analysis of Arrival Time Distributions in Ion Mobility Mass Spectrometry

AbstractIon mobility‐mass spectrometry (IM‐MS) has recently contributed to the structural analysis of molecules, including supramolecules and proteins, by determining the ion arrival time distributions correlated with the collision cross sections (CCSs), as well as the mass‐to‐charge ratios. However, its application range is still limited owing to the lack of general CCSs simulation methods based on possible molecular conformations. Here, a molecular dynamics‐based conformational search method for simulating CCS distributions using projection approximation is reported. As a case study, the gas‐phase conformations of the sodium adducts of conformationally flexible polyketones with 3,3‐dimethylpentane‐2,4‐dione as the monomer are analyzed. The sodium adduct of the hexamer (m/z 781.4 for [1 + Na]+) showed a monomodal arrival time distribution, but that of the octamer sodium adduct (m/z 1033.5 for [2 + Na]+) is multimodal. The conformational analysis indicated an unimodal CCS distribution of simulated [1 + Na]+ conformations in which the sodium cation is mainly bound at the chain terminal. Conversely, four clusters of conformations are obtained for [2 + Na]+ based on the Na+‐coordination sites, which qualitatively reproduced the observed CCS distribution. This approach will extend the utility of IM‐MS for the conformational analysis of flexible molecules in the gas phase.

Theoretical Mechanistic Investigation of the Dynamic Kinetic Resolution of N-Protected Amino Acid Esters using Phase-Transfer Catalysts.

A detailed theoretical mechanistic investigation on the dynamic kinetic resolution of N-protected amino acid esters using phase-transfer catalysts is described. Semiautomatic exhaustive conformation search of transition state (TS)-like structures were carried out using the ConFinder program and the pseudo-TS conformational search (PTSCS) method. This conformational search method successfully provided reasonable TS structures for determining the stereoselectivity in the asymmetric base hydrolysis of hexafluoroisopropyl (HFIP) esters as well as the racemization mechanism. Furthermore, the independent gradient model (IGM) analysis of the TS structures suggested that the H-bonding interactions with the oxyanion hole and π-stacking interactions are the common important features of the proposed TS structures that determine the stereoselectivity.

Analysis of the sidechain structures of amino acids and peptides and a deduced method for the efficient search of peptide conformations

To reduce the dimensionality of the potential energy surface (PES) necessary for finding the low energy conformations (LECs) of peptides, the sidechain dihedral angles (DAs) of 3548 LECs of 17 amino acids (AAs) and related peptides are examined. The analysis reveals that most DAs can be discretized into 3 states. Moreover, the fact that many DA combinations are absent in the LECs is utilized to construct a new conformational search method named as the TM method. For a peptide with N AA residues, the TM method is 1.5N times faster than considering all DA combinations, and 4.7N times faster than the conventional Newman projection method. The reliability of the TM results is confirmed through testing on 11 dipeptides and 2 tetrapeptides. The much reduced PES size of the TM method allows the database building of diverse peptide structures, and enhances the reliability of various stochastic sampling based methods.

Conformational Study of the Structure of dibenzo-18-crown-6. Comparison with 18-crown-6

We report for the first time the conformational analysis of dibenzo-18-crown-6, db18c6. The conformational search was carried out using the CONFLEX conformational search method of cyclic molecules. Energies were calculated for the low-lying predicted conformations at different levels of theory up to the G3MP2 level. At the G3MP2 level, the predicted ground state (GS) conformation was more stable than the experimental conformation by only 1.60kcal/mol. Strong similarity was found between the GS structure and experimental conformations of db18c6 and 18-crown-6, 18c6. The GS and experimental conformations of db18c6 are non-planar. This allows db18c6 to exist in optically active enantiomers. Similar to 18c6, it was concluded that the db18c6 structure is stabilized by intramolecular hydrogen bond. We also performed the computations for the water and chloroform solution phase, where the same conformation was predicted as the GS conformation.

Efficient Conformational Search Based on Structural Dissimilarity Sampling: Applications for Reproducing Structural Transitions of Proteins.

Structural Dissimilarity Sampling (SDS) is proposed as an efficient conformational search method to promote structural transitions essential for the biological functions of proteins. In SDS, initial structures are selected based on structural dissimilarity, and conformational resampling is repeated. Conformational resampling is performed as follows: (I) arrangement of initial structures for a diverse distribution at the edge of a conformational subspace and (II) promotion of the structural transitions with multiple short-time molecular dynamics (MD) simulations restarting from the diversely distributed initial structures. Cycles of (I) and (II) are repeated to intensively promote structural transitions because conformational resampling from the initial structures would quickly expand conformational distributions toward unvisited conformational subspaces. As a demonstration, SDS was first applied to maltodextrin binding protein (MBP) in explicit water to reproduce structural transitions between the open and closed states of MBP. Structural transitions of MBP were successfully reproduced with SDS in nanosecond-order simulation times. Starting from both the open and closed forms, SDS successfully reproduced the structural transitions within 25 cycles (a total of 250 ns of simulation time). For reference, a conventional long-time (500 ns) MD simulation under NPT (300 K and 1 bar) starting from the open form failed to reproduce the structural transition. In addition to the open-closed motions of MBP, SDS was applied to folding processes of the fast-folding proteins (chignolin, Trp-cage, and villin) and successfully sampled their native states. To confirm how the selections of initial structures affected conformational sampling efficiency, numbers of base sets for characterizing structural dissimilarity of initial structures were addressed in distinct trials of SDS. The parameter searches showed that the conformational sampling efficiency was relatively insensitive with respect to the numbers of base sets, indicating the robustness of SDS for actual applications.

A New Efficient Conformational Search Method for ab initio Protein Folding Study: Window Growth Evolutionary Algorithm

A new conformational search method, WGEA (window growth evolutionary algorithm), is described. In this method, a trial conformation is selected or rejected on the basis of the energy of a selected window of w consecutive residues only; interactions between residues beyond the selected window are ignored. The position of the window is selected randomly in a Monte‐Carlo procedure. The window size w is changed slowly, from a minimum of 6 to the full length of the protein. An ensemble of structures is generated at each window size from which a fixed number of conformations are selected to be used as seed conformations for the next window size. When the root‐mean‐square (RMS) deviation from the experimental structure is used as the energy function and six discrete dihedral angle states are used for each residue to describe the protein conformation, WGEA efficiently refolds 14 model proteins within Cα RMS deviation of 1.2–2.8 Å.

Conformational analysis of 9-crown-3, 9-thiacrown-3 and 9-azacrown-3

Crown ethers are an important class of molecules with wide applications. Crown ethers are large ring flexible molecules with a large number of possible conformations. In the current manuscript, we report the conformational analysis results of one of the smallest crown ether systems, namely, 9-crown-3, 9c3, 9-thiacrown-3, 9t3, and 9-azacrown-3, 9a3. The conformational search is performed using the CONFLEX conformational search method utilizing the MMFF94s force field. 8, 11 and 62 conformations were predicted for 9c3, 9t3 and 9a3, respectively. The ab initio computations were performed at B3LYP and MP2 levels using the 6–311G** basis set. For the accurate prediction of the ground state conformation and the energy order of the low-lying energy conformations, the computations were performed at the G4 level for some selected conformations. Factors affecting the stability of different conformations of 9c3, 9t3 and 9a3 are discussed. These factors are also discussed with respect to larger crown ether systems. The ab initio computations were performed also for water and chloroform as solution phases. The same ground state predicted in the gas phase was also predicted in the solution water and chloroform phases.

Molecular Simulations of Protein Systems toward Drug Discovery

Molecular simulations have been widely used in biomolecular systems such as proteins, DNA, etc. The search for stable conformations of proteins by molecular simulations is important to understand the function and stability of proteins. However, finding the stable state by conformational search is difficult, because the energy landscape of the system is characterized by many local minima separated by high energy barriers. In order to overcome this difficulty, various sampling and optimization methods for the conformation of proteins have been proposed. In this study, we propose a new conformational search method for proteins based on a genetic algorithm. We applied this method to an α-helical protein. We found that the conformations obtained from our simulations are in good agreement with the experimental results.

Enhanced conformational sampling method for proteins based on the TaBoo SeArch algorithm: application to the folding of a mini-protein, chignolin.

The conformational samplings are indispensible for obtaining reliable canonical ensembles, which provide statistical averages of physical quantities such as free energies. However, the samplings of vast conformational space of biomacromolecules by conventional molecular dynamics (MD) simulations might be insufficient, due to their inadequate accessible time-scales for investigating biological functions. Therefore, the development of methodologies for enhancing the conformational sampling of biomacromolecules still remains as a challenging issue in computational biology. To tackle this problem, we newly propose an efficient conformational search method, which is referred as TaBoo SeArch (TBSA) algorithm. In TBSA, an inverse energy histogram is used to select seeds for the conformational resampling so that states with high frequencies are inhibited, while states with low frequencies are efficiently sampled to explore the unvisited conformational space. As a demonstration, TBSA was applied to the folding of a mini-protein, chignolin, and automatically sampled the native structure (Cα root mean square deviation < 1.0 Å) with nanosecond order computational costs started from a completely extended structure, although a long-time 1-µs normal MD simulation failed to sample the native structure. Furthermore, a multiscale free energy landscape method based on the conformational sampling of TBSA were quantitatively evaluated through free energy calculations with both implicit and explicit solvent models, which enable us to find several metastable states on the folding landscape.

&lt;Review&gt; A Mini-review on Chemoinformatics Approaches for Drug Discovery

We have reviewed chemoinformatics approaches for drug discovery such as aromatic interactions, aromatic clusters, structure generation, virtual screening, de novo design, evolutionary algorithm, inverse-QSPR/QSAR, Monte Carlo, molecular dynamics, fragment molecular orbital method and matched molecular pair analysis from the viewpoint of young researchers. We intend to introduce various fields of chemoinformatics for non-expert researchers. The structure of this review is given as follows: 1. Introduction, 2. Analysis of Aromatic Interactions, 2.1 Aromatic Interactions, 2.2 Aromatic Clusters, 3. Ligand Based Structure Generation, 3.1 Virtual Screening, 3.2 De Novo Ligand Design, 3.3 Combinatorial Explosion, 3.4 Inverse-QSPR/QSAR, 4. Trends in Chemoinformatics-Based De Novo Drug Design, 5. Conformational Search Method Using Genetic Crossover for Bimolecular Systems, 6. Interaction Analysis using Fragment Molecular Orbital Method for Drug Discovery, 7. Matched Molecular Pair Analysis and SAR Analysis by Fragment Molecular Orbital Method, 8. Chemoinformatics Approach in Pharmaceutical Processes, 9. Conclusion.

Exploring conformational search protocols for ligand-based virtual screening and 3-D QSAR modeling.

3-D ligand conformations are required for most ligand-based drug design methods, such as pharmacophore modeling, shape-based screening, and 3-D QSAR model building. Many studies of conformational search methods have focused on the reproduction of crystal structures (i.e. bioactive conformations); however, for ligand-based modeling the key question is how to generate a ligand alignment that produces the best results for a given query molecule. In this work, we study different conformation generation modes of ConfGen and the impact on virtual screening (Shape Screening and e-Pharmacophore) and QSAR predictions (atom-based and field-based). In addition, we develop a new search method, called common scaffold alignment, that automatically detects the maximum common scaffold between each screening molecule and the query to ensure identical coordinates of the common core, thereby minimizing the noise introduced by analogous parts of the molecules. In general, we find that virtual screening results are relatively insensitive to the conformational search protocol; hence, a conformational search method that generates fewer conformations could be considered "better" because it is more computationally efficient for screening. However, for 3-D QSAR modeling we find that more thorough conformational sampling tends to produce better QSAR predictions. In addition, significant improvements in QSAR predictions are obtained with the common scaffold alignment protocol developed in this work, which focuses conformational sampling on parts of the molecules that are not part of the common scaffold.

Macrocycle Conformational Sampling with MacroModel

Sampling low energy conformations of macrocycles is challenging due to the large size of many of these molecules and the constraints imposed by the macrocycle. We present a new conformational search method (implemented in MacroModel) that uses brief MD simulations followed by minimization and normal-mode search steps. The method was parametrized using a set of 100 macrocycles from the PDB and CSD. It was then tested on a publicly available data set for which there are published results using alternative methods; we found that when the same force field is used (in this case MMFFs in vacuum), our method tended to identify conformations with lower energies than what the other methods identified. The performance on a new set of 50 macrocycles from the PDB and CSD was also quite good; the mean and median RMSD values for just the ring atoms were 0.60 and 0.33 Å, respectively. However, the RMSD values for macrocycles with more than 30 ring-atoms were quite a bit larger compared to the smaller macrocycles. Possible origins for this and ideas for improving the performance on very large macrocycles are discussed.

ChemInform Abstract: Enantioselective Alkylation by Binaphthyl Chiral Phase‐Transfer Catalysts: A DFT‐Based Conformational Analysis.

A conformational search method based on the density functional theory (DFT) was successfully applied to explore a mechanism for the highly enantioselective alkylation by binaphthyl-modifed chiral phase-transfer catalysts. Key interactions that govern the enantioselectivity were analyzed. The computational results are encouraging for further application of the DFT-based conformational search toward the rational design of next-generation asymmetric phase transfer catalysts.

A Conformational Search Method for Protein Systems Using Genetic Crossover and Metropolis Criterion

Many proteins carry out their biological functions by forming the characteristic tertiary structures. Therefore, the search of the stable states of proteins by molecular simulations is important to understand their functions and stabilities. However, getting the stable state by conformational search is difficult, because the energy landscape of the system is characterized by many local minima separated by high energy barriers. In order to overcome this difficulty, various sampling and optimization methods for conformations of proteins have been proposed. In this study, we propose a new conformational search method for proteins by using genetic crossover and Metropolis criterion. We applied this method to an α-helical protein. The conformations obtained from the simulations are in good agreement with the experimental results.

Enantioselective Alkylation by Binaphthyl Chiral Phase-Transfer Catalysts: A DFT-Based Conformational Analysis

A conformational search method based on the density functional theory (DFT) was successfully applied to explore a mechanism for the highly enantioselective alkylation by binaphthyl-modifed chiral phase-transfer catalysts. Key interactions that govern the enantioselectivity were analyzed. The computational results are encouraging for further application of the DFT-based conformational search toward the rational design of next-generation asymmetric phase transfer catalysts.

Evaluations of the conformational search accuracy of CAMDAS using experimental three-dimensional structures of protein-ligand complexes

CAMDAS is a conformational search program, through which high temperature molecular dynamics (MD) calculations are carried out. In this study, the conformational search ability of CAMDAS was evaluated using structurally known 281 protein-ligand complexes as a test set. For the test, the influences of initial settings and initial conformations on search results were validated. By using the CAMDAS program, reasonable conformations whose root mean square deviations (RMSDs) in comparison with crystal structures were less than 2.0 Å could be obtained from 96% of the test set even though the worst initial settings were used. The success rate was comparable to those of OMEGA, and the errors of CAMDAS were less than those of OMEGA. Based on the results obtained using CAMDAS, the worst RMSD was around 2.5 Å, although the worst value obtained was around 4.0 Å using OMEGA. The results indicated that CAMDAS is a robust and versatile conformational search method and that it can be used for a wide variety of small molecules. In addition, the accuracy of a conformational search in relation to this study was improved by longer MD calculations and multiple MD simulations.

Gas Phase Conformations of Tetrapeptide Glycine-Phenylalanine-Glycine-Glycine

Systematic search of the potential energy surface of tetrapeptide glycine-phenylalanine-glycine-glycine (GFGG) in gas phase is conducted by a combination of PM3, HF and BHandHLYP methods. The conformational search method is described in detail. The relative electronic energies, zero point vibrational energies, dipole moments, rotational constants, vertical ionization energies and the temperature dependent conformational distributions for a number of important conformers are obtained. The structural characteristics of these conformers are analyzed and it is found that the entropic effect is a dominating factor in determining the relative stabilities of the conformers. The measurements of dipole moments and some characteristic IR mode are shown to be effective approaches to verify the theoretical prediction. The structures of the low energy GFGG conformers are also analyzed in their connection with the secondary structures of proteins. Similarity between the local structures of low energy GFGG conformers and the α-helix is discussed and many β- and γ-turn local structures in GFGG conformers are found.

Protein structure predictions by parallel simulated annealing molecular dynamics using genetic crossover

We propose a conformational search method to find a global minimum energy structure for protein systems. The simulated annealing is a powerful method for local conformational search. On the other hand, the genetic crossover can search the global conformational space. Our method incorporates these attractive features of the simulated annealing and genetic crossover. In the previous works, we have been using the Monte Carlo algorithm for simulated annealing. In the present work, we use the molecular dynamics algorithm instead. To examine the effectiveness of our method, we compared our results with those of the normal simulated annealing molecular dynamics simulations by using an α-helical miniprotein. We used genetic two-point crossover here. The conformations, which have lower energy than those obtained from the conventional simulated annealing, were obtained.

ConfGen: A Conformational Search Method for Efficient Generation of Bioactive Conformers

We describe the methodology, parametrization, and application of a conformational search method, called ConfGen, designed to efficiently generate bioactive conformers. We define efficiency as the ability to generate a bioactive conformation within a small total number of conformations using a reasonable amount of computer time. The method combines physics-based force field calculations with empirically derived heuristics designed to achieve efficient searching and prioritization of the ligand's conformational space. While many parameter settings are supported, four modes spanning a range of speed and quality trades-offs are defined and characterized. The validation set used to test the method is composed of ligands from 667 crystal structures covering a broad array of target and ligand classes. With the fastest mode, ConfGen uses an average of 0.5 s per ligand and generates only 14.3 conformers per ligand, at least one of which lies within 2.0 A root-mean-squared deviation of the crystal structure for 96% of the ligands. The most computationally intensive mode raises this recovery rate to 99%, while taking 8 s per ligand. Combining multiple search modes to "fill-in" holes in the conformation space or energy minimizing using an all-atom force field each lead to improvements in the recovery rates at higher resolutions. Overall, ConfGen is at least as good as competing programs at high resolution and demonstrates higher efficiency at resolutions sufficient for many downstream applications, such as pharmacophore modeling.

Conformational Analysis of a Model for the trans-Fused FGH Ether Rings in Brevetoxin A

We have applied the Low Mode:Monte Carlo (LM:MC) conformational search method to an investigation of the low energy structures for 3R,4aS,7aR,11aS,12aR)-11a-methyl-3-phenyldecahydro-1H-[1,3]dioxino[5,4-b]pyrano[2,3-g]oxocine, 3, a model for the FGH rings in brevetoxin A, a potent marine toxin. Searches performed using a variety of classical force field-solvent combinations yielded ensembles containing between 30 and 60 structures with the central G-ring adopting the crown, twist-crown, boat-chair, and boat conformations. The lowest energy structure depended on the force field-solvent treatment, and the twist-crown and boat-chair conformers were typically lowest in energy. B3LYP/6-31G** geometry optimizations using the SCRF continuum solvent model confirmed these structures but indicated that the crown was the energetically preferred conformer with the boat-chair lying within 1.4 kcal/mol.