On the interpretation of residual dipolar couplings as reporters of molecular dynamics

The analysis of residual dipolar couplings from an ensemble of conformations to extract molecular dynamics is intricate. The very mechanism that is necessary to perturb overall molecular tumbling to generate nonvanishing residual dipolar couplings gives rise to convoluted data. The measured values are essentially weighted averages over conformations. However, the weights are not simply the populations of conformations. Consequently, the observed order parameter is not exactly the true measure of motion. In the case of paramagnetic alignment, the apparent order parameter is expected to depend on the number of torsions that separate the locus of interest from the paramagnetic site. In the case of alignment due to steric obstruction, the uneven selection of conformations by their differing Saupe order matrices leads to a bias in the residual dipolar couplings-probed molecular dynamics.     

Enhanced efficiency of direct-space structure solution from powder X-ray diffraction data in the case of conformationally flexible molecules

A strategy is reported for assessing the feasibility of molecular conformations within direct-space structure-solution calculations of organic molecular crystal structures from powder X-ray diffraction data, focusing in particular on the genetic algorithm technique for structure solution in which fitness is defined as a function of the whole-profile figure-of-merit Rwp. The strategy employs a readily computed distance-based function to assess the feasibility of the molecular conformation in each trial structure generated in the genetic algorithm calculation, and structures considered to have low-feasibility conformations are penalized within the evolutionary process. The strategy is shown to lead to significant improvements in the success rate of structure-solution calculations in the case of flexible molecules with a significant number of conformational degrees of freedom.     

The conformation of alkyl sulfoxides

Parameters for sulfoxides used in force field MM1 were modified to be incorporated into force field MM2. The conformations of ten alkyl sulfoxides were then calculated using MM2 with these new parameters. The alkyl groups used were methyl, ethyl, isopropyl, and t-butyl. It was found that of the many possible conformations for these compounds, only one or two stable conformers exist, and that the number of these conformers agrees with the number of reported S? O stretching frequencies in almost every case. No apparent correlation between the vibration frequency and the molecular structure was found.     

Fuzzy clustering as a means of selecting representative conformers and molecular alignments

This paper describes the first application of fuzzy c-means clustering for the selection of representatives from assemblies of conformations or alignments. In case of alignments, their quality is taken into account using a weighted c-means scheme, developed in this work. The performance of fuzzy cluster validity measures, such as compactness, partition function, and entropy, are studied on several examples, but the visual 3D representation of data points is shown to be most beneficial in determining the optimum number of clusters. Fuzzy clustering is expected to perform better than crisp clustering methods in cases where there are a significant number of "outliers", such as in molecular dynamics simulations and molecular alignments.     

A new method for fast and accurate derivation of molecular conformations

During molecular simulations, three-dimensional conformations of biomolecules are calculated from the values of their bond angles, bond lengths, and torsional angles. In this paper we study how to efficiently derive three-dimensional molecular conformations from the values of torsional angles. This case is of broad interest as torsional angles greatly affect molecular shape and are always taken into account during simulations. We first review two widely used methods for deriving molecular conformations, the simple rotations scheme and the Denavit-Hartenberg local frames method. We discuss their disadvantages which include extensive bookkeeping, accumulation of numerical errors, and redundancies in the local frames used. Then we introduce a new, fast, and accurate method called the atomgroup local frames method. This new method not only eliminates the disadvantages of earlier approaches but also provides lazy evaluation of atom positions and reduces the computational cost. Our method is especially useful in applications where many conformations are generated or updated such as in energy minimization and conformational search.     

A peptide co-solvent under scrutiny: self-aggregation of 2,2,2-trifluoroethanol

Trifluoroethanol (TFE) and its aggregates are studied via supersonic jet FTIR and Raman spectroscopy as well as by quantum chemistry and simple force field approaches. A multi-slit nozzle is introduced to study collisionally excited clusters. Efforts are made to extract harmonic frequencies from experiment for better comparison to theory. Based on deuteration, the OH stretching anharmonicity changes weakly upon dimerization, but increases for trimers. Among the possible dimer conformations, only an all-gauche, homoconfigurational, compact, OH-F connected structure is observed in an extreme case of chiral discrimination. Quantum tunneling assisted pathways for this surprising helicity synchronization are postulated. The oscillator coupling in hydrogen-bonded trimers is analyzed. Trans conformations of TFE start to become important for trimers and probably persist in the liquid state. Simple force fields can be refined to capture some molecular recognition features of TFE dimer, but their limitations are emphasized.     

Flexible Molecules with Defined Shape—Conformational Design

Chemists have for a long time considered molecules simply in terms of their constitution. The importance of molecular shape was recognized perhaps for the first time by the semio-chemists, who were interested in the interactions of fragrant substances with a receptor. Apart from the case of rigid molecules, our ideas and concepts of molecular shape simply reflect an instantaneous situation, because flexible molecules take advantage of the whole range of conformation that is available to them. Nature frequently utilizes flexible molecules whose conformational space is restricted, in other words, molecules that can adopt only a few preferred conformations. This review discusses some of the principles that nature employs in order to impart a defined shape to flexible molecules. The purposeful application of these principles then allows the conformational design of molecular skeletons. For corrigendum see DOI: 10.1002/anie.199215401 For corrigendum see DOI: 10.1002/anie.199216571     

Quantifying polypeptide conformational space: sensitivity to conformation and ensemble definition

Quantifying the density of conformations over phase space (the conformational distribution) is needed to model important macromolecular processes such as protein folding. In this work, we quantify the conformational distribution for a simple polypeptide (N-mer polyalanine) using the cumulative distribution function (CDF), which gives the probability that two randomly selected conformations are separated by less than a "conformational" distance and whose inverse gives conformation counts as a function of conformational radius. An important finding is that the conformation counts obtained by the CDF inverse depend critically on the assignment of a conformation's distance span and the ensemble (e.g., unfolded state model): varying ensemble and conformation definition (1 --> 2 A) varies the CDF-based conformation counts for Ala(50) from 10(11) to 10(69). In particular, relatively short molecular dynamics (MD) relaxation of Ala(50)'s random-walk ensemble reduces the number of conformers from 10(55) to 10(14) (using a 1 A root-mean-square-deviation radius conformation definition) pointing to potential disconnections in comparing the results from simplified models of unfolded proteins with those from all-atom MD simulations. Explicit waters are found to roughen the landscape considerably. Under some common conformation definitions, the results herein provide (i) an upper limit to the number of accessible conformations that compose unfolded states of proteins, (ii) the optimal clustering radius/conformation radius for counting conformations for a given energy and solvent model, (iii) a means of comparing various studies, and (iv) an assessment of the applicability of random search in protein folding.     

Different approaches to conformational analysis: A comparison of completeness,efficiency, and reliability based on the study of a nine-membered lactam

Different methods such as molecular dynamics, systematic, or stochastic search and a special “generic shape” algorithm have been employed in the conformational analysis of a nine-membered lactam. Furthermore, crystal data were used to generate conformations of the compound under consideration. The various methods are compared in terms of their efficiency and completeness in the search for conformations with an energy content of up to 60 kJ/mol above the global minimum. Additionally, the generated conformations have been optimized by different techniques, molecular mechanics and quantum chemical calculations, to compare the number of existing local minima and their relative energies and geometries.     

Calculation of number and free energy of the conformers of linear alkanes with medium and long chains. Implications for catalysis

A method for calculating the number of rotamers of a linear alkane and of the number of rotamers with a given number of gauche conformations along the chain as a function of the total number of atoms in the chain, using general equations, is presented. A graphical method for generating individual rotamers was applied to the homologs up to decane, which has 1134 rotamers. The steric energies calculated by molecular mechanics (MM2 force field) were used as measures of the heat of formation for the coiled conformations relative to the anti conformer for each molecule, whereas the statistical entropy differences were calculated for classes of coiled rotamers grouped by the number of gauche bonds and steric energy. The free energy values calculated from these components show that already at 400 K hexane exists preferentially in conformations containing gauche bonds. For larger chains the free energy advantage for the coiled chains increases very steeply. The implications for the question of reactions of linear alkanes occurring on the surface or inside the channels of small- and medium-pore zeolites are briefly examined.     

Enhanced sampling method in molecular simulations using genetic algorithm for biomolecular systems

We propose a molecular simulation method using genetic algorithm (GA) for biomolecular systems to obtain ensemble averages efficiently. In this method, we incorporate the genetic crossover, which is one of the operations of GA, to any simulation method such as conventional molecular dynamics (MD), Monte Carlo, and other simulation methods. The genetic crossover proposes candidate conformations by exchanging parts of conformations of a target molecule between a pair of conformations during the simulation. If the candidate conformations are accepted, the simulation resumes from the accepted ones. While conventional simulations are based on local update of conformations, the genetic crossover introduces global update of conformations. As an example of the present approach, we incorporated genetic crossover to MD simulations. We tested the validity of the method by calculating ensemble averages and the sampling efficiency by using two kinds of peptides, ALA3 and (AAQAA)₃. The results show that for ALA3 system, the distribution probabilities of backbone dihedral angles are in good agreement with those of the conventional MD and replica-exchange MD simulations. In the case of (AAQAA)₃ system, our method showed lower structural correlation of α-helix structures than the other two methods and more flexibility in the backbone ψ angles than the conventional MD simulation. These results suggest that our method gives more efficient conformational sampling than conventional simulation methods based on local update of conformations. © 2018 Wiley Periodicals, Inc.     

Accessing Improbable Foldamer Shapes with Strained Macrocycles

The alkylation of some secondary amide functions with a dimethoxybenzyl (DMB) group in oligomers of 8-amino-2-quinolinecarboxylic acid destabilizes the otherwise favored helical conformations, and allows for cyclization to take place. A cyclic hexamer and a cyclic heptamer were produced in this manner. After DMB removal, X-ray crystallography and NMR show that the macrocycles adopt strained conformations that would be improbable in noncyclic species. The high helix folding propensity of the main chain is partly expressed in these conformations, but it remains frustrated by macrocyclization. Despite being homomeric, the macrocycles possess inequivalent monomer units. Experimental and computational studies highlight specific fluxional pathways within these structures. Extensive simulated annealing molecular dynamics allow for the prediction of the conformations for larger macrocycles with up to sixteen monomers.     

Novel Big Data-Driven Machine Learning Models for Drug Discovery Application

Most contemporary drug discovery projects start with a ‘hit discovery’ phase where small chemicals are identified that have the capacity to interact, in a chemical sense, with a protein target involved in a given disease. To assist and accelerate this initial drug discovery process, ’virtual docking calculations’ are routinely performed, where computational models of proteins and computational models of small chemicals are evaluated for their capacities to bind together. In cutting-edge, contemporary implementations of this process, several conformations of protein targets are independently assayed in parallel ‘ensemble docking’ calculations. Some of these protein conformations, a minority of them, will be capable of binding many chemicals, while other protein conformations, the majority of them, will not be able to do so. This fact that only some of the conformations accessible to a protein will be ’selected’ by chemicals is known as ’conformational selection’ process in biology. This work describes a machine learning approach to characterize and identify the properties of protein conformations that will be selected (i.e., bind to) chemicals, and classified as potential binding drug candidates, unlike the remaining non-binding drug candidate protein conformations. This work also addresses the class imbalance problem through advanced machine learning techniques that maximize the prediction rate of potential protein molecular conformations for the test case proteins ADORA2A (Adenosine A2a Receptor) and OPRK1 (Opioid Receptor Kappa 1), and subsequently reduces the failure rates and hastens the drug discovery process.     

Hydrodynamic and conformational properties of cellulose valerate molecules in dilute solution

Using the methods of molecular hydrodynamics, structural-conformational studies have been performed for a number of cellulose valerate and acetovalerate samples in the molecular-mass range M = (58.1–464.3) × 10³ and with a mean degree of substitution of 182.4 with respect to valeric acid isomers. The conformations of valerate-substituted cellulose molecules are characterized by an increased local packing density of monomer units. The molecular conformations are quantitatively described in terms of the helix formed by the succession of vectors connecting glycoside oxygens of a chain. The molecular-hydrodynamic and conformational characteristics of cellulose valerate are compared with the corresponding characteristics of cellulose myristate.     

Conformational analysis: a new approach by means of chemometrics

In conformational analysis, the systematic search method completely maps the space but suffers from the combinatorial explosion problem because the number of conformations increases exponentially with the number of free rotation angles. This study introduces a new methodology of conformational analysis that controls the combinatorial explosion. It is based on a dimensional reduction of the system through the use of principal component analysis. The results are exactly the same as those obtained for the complete search but, in this case, the number of conformations increases only quadratically with the number of free rotation angles. The method is applied to a series of three drugs: omeprazole, pantoprazole, lansoprazole-benzimidazoles that suppress gastric-acid secretion by means of H+, K+-ATPase enzyme inhibition.     

Ab initio studies of structural features not easily amenable to experiment : Part 24. Molecular structures and conformational analyses of the methyl esters of formic acid, acetic acid and alanine

The molecular structures of four conformations of methyl formate, of two conformations, each, of methyl acetate and methyl alanate have been determined by ab initio force relaxation on the 4-21G level. Relative stabilities and some selected structural aspects are discussed.     

All‐Atom Molecular Dynamics Simulation of Structure and Diffusion of Hydrophilic Antistatic Agents in Polypropylene

Glycerol monostearate (GMS) is an additive widely used in plastic industry for its good ability to improve the wettability and antistatic property of polymer surfaces. Based on GMS, we propose five additives of different polarity by attuning the number of oxyethyl groups. All‐atom molecular dynamics simulations of these additives in polypropylene (PP) matrix are carried out at temperatures of 300 K, 350 K and 400 K. Detailed molecular conformations are obtained and analyzed. Due to the gauche effect of the dihedral angles, the polar parts of these additives form helix structures. The diffusion coefficient of the additives depends on their molecular conformations and decreases monotonously with increasing polarity. These results are expected to be helpful in rational design of hydrophilic antistatic agents in polymeric materials.     

Weak attractive interactions between methylthio groups and electron-deficient alkenes in peri-naphthalenes: a competition with conjugative effects

The solid-state conformations of five peri-disubstituted naphthalenes bearing a methylthio group and an electron-deficient alkene indicate a weak attractive interaction between the functional groups in four cases in which out-of-plane displacements lead to a common orientation of the MeSsp(2)-C vector to the alkene bond. In some cases the interaction is not strong enough to outweigh the tendency of the alkene to conjugate with the aromatic ring, and in one case this optimisation of conjugation alone controls the molecular conformation. The methylthio group lies close to the aromatic plane in all but one example for which the plane of the sulfide group is presented to the alkene.