Conformational analysis by scaled energy embedding

Distance geometry has been used for some years to find conformations of molecules consistent with given bounds on the interatomic distances. A recent extension of the method, called energy embedding, enforces the geometric constraints as before, but also biases the results toward low-energy structures. Now a significant improvement on energy embedding is presented, which is less dependent on local optimization for satisfying the geometric constraints. Tests on very small systems with well understood energy functions show that the global minimum energy value is often attained, and geometric constraints are always satisfied.     

Q-fit: a probabilistic method for docking molecular fragments by sampling low energy conformational space

A new method is presented that docks molecular fragments to a rigid protein receptor. It uses a probabilistic procedure based on statistical thermodynamic principles to place ligand atom triplets at the lowest energy sites. The probabilistic method ranks receptor binding modes so that the lowest energy ones are sampled first. This allows constraints to be introduced to limit the depth of the search leading to a computationally efficient method of sampling low energy conformational space. This is combined with energy minimization of the initial fragment placement to arrive at a low energy conformation for the molecular fragment. Two different search methods are tested involving (i) geometric hashing and (ii) pose clustering methods. Ten molecular fragments were docked that have commonly been used to test docking methods. The success rate was 8/10 and 10/10 for generating a close solution ranked first using the two different sampling procedures. In general, all five of the top ranked solutions reproduce the observed binding mode, which increases confidence in the predictions. A set of ten molecular fragments that have previously been identified as problematic were docked. Success was achieved in 3/10 and 4/10 using the two different methods. Again there is a high level of agreement between the two methods and again in the successful cases the top ranked solutions are correct whilst in the case of the failures none are. The geometric hashing and pose clustering methods are fast averaging 13 and 11 s per placement respectively using conservative parameters. The results are very encouraging and will facilitate the process of finding novel small molecule lead compounds by virtual screening of chemical databases.     

Optically controlled resonance energy transfer: mechanism and configuration for all-optical switching

In a molecular system of energy donors and acceptors, resonance energy transfer is the primary mechanism by means of which electronic energy is redistributed between molecules, following the excitation of a donor. Given a suitable geometric configuration it is possible to completely inhibit this energy transfer in such a way that it can only be activated by application of an off-resonant laser beam: this is the principle of optically controlled resonance energy transfer, the basis for an all-optical switch. This paper begins with an investigation of optically controlled energy transfer between a single donor and acceptor molecule, identifying the symmetry and structural constraints and analyzing in detail the dependence on molecular energy level positioning. Spatially correlated donor and acceptor arrays with linear, square, and hexagonally structured arrangements are then assessed as potential configurations for all-optical switching. Built on quantum electrodynamical principles the concept of transfer fidelity, a parameter quantifying the efficiency of energy transportation, is introduced and defined. Results are explored by employing numerical simulations and graphical analysis. Finally, a discussion focuses on the advantages of such energy transfer based processes over all-optical switching of other proposed forms.     

A method for constrained energy minimization of macromolecules

Two algorithms for the local energy minimization of the structure of macromolecules in the presence of constraints are proposed. They are a combination of the method of steepest descents and the method of conjugate gradients with the procedure SHAKE, by which distance constraints can be satisfied. The two algorithms are tested by applying them to a small protein, the bovine pancreatic trypsin inhibitor (BPTI), and compared with the penalty function method for conserving constraints. The efficiency of the proposed methods depends on the level of interdependence of the constraints. For bond-length constraints, the use of SHAKE is superior to the penalty function method. However, when bond-angle constraints are included, SHAKE is more efficient only if the curvature of the penalty function is considerably greater than that of the potential function being minimized. The results indicate that with bond-length constraints the minimization behavior is similar to that without constraints. However, the simultaneous application of bond-length and bond-angle constraints appears to confine the molecule to a very limited part of configuration space, very different from the part covered by an unconstrained minimization. This conclusion calls into question energy minimizations of protein systems in which only the dihedral angles are allowed to vary.     

Conformational sampling by self-organization

A new stochastic algorithm for conformational sampling is described. The algorithm generates molecular conformations that are consistent with a set of geometric constraints, which include interatomic distance bounds and chiral volumes derived from the molecular connectivity table. The algorithm repeatedly selects individual geometric constraints at random and updates the respective atomic coordinates toward satisfying the chosen constraint. When compared to a conventional distance geometry algorithm based on the same set of geometric constraints, our method is faster and generates conformations that are more diverse and more energetically favorable.     

Method for the design of broad energy range focusing reflectrons

A novel method for the design of reflections capable of focusing large kinetic energy ranges is presented. The design method itself is a numerical approach that provides a geometrically flexible alternative to traditional analytical design solutions. This design method has been used to produce a reflectron that provides unit mass resolution for product spectra in a tandem reflectron time-of-flight (TOF) mass spectrometer despite a kinetic energy range of 1950–2700 eV. In this application, the systematic progression of reflectron design results in a practical, nonlinear field reflectron with the use of only two grids. Design improvements are proposed for more flexible systems, although geometric constraints in the current instrument limit their experimental evaluation.     

The ellipsoid algorithm as a method for the determination of polypeptide conformations from experimental distance constraints and energy minimization

A new method for constrained nonlinear optimization known as the ellipsoid algorithm is evaluated as a means of determining and refining the conformations of peptides. Advantages of the ellipsoid algorithm over conventional optimization methods include that it avoids many local minima that other methods would be trapped by, and that it is sometimes able to find optimum solutions in which the constraints are satisfied exactly. The dihedral angles about single bonds were used as variables to keep the dimensionality low (the rate of convergence decreases rapidly with increasing dimensionality of the problem). The method is evaluated on problems involving distance constraints, and for minimization of conformational energy functions. In an initial application, conformations consistent with an experimental set of NMR distance constraints were obtained in a problem involving 48 variable dihedral angles.     

Self-organizing superimposition algorithm for conformational sampling

A novel self-organizing algorithm for conformational sampling is introduced, in which precomputed conformations of rigid fragments are used as templates to enforce the desired geometry. Starting from completely random coordinates, the algorithm repeatedly superimposes the templates to adjust the positions of the atoms, thereby gradually refining the conformation of the molecule. Combined with pair-wise adjustments of the atoms to resolve steric clashes, conformations that satisfy all geometric constraints can be generated from this procedure. The algorithm is demonstrated to achieve good performance and promises potential applications on more challenging modeling problems.     

Geometric algorithms for the conformational analysis of long protein loops

The efficient filtering of unfeasible conformations would considerably benefit the exploration of the conformational space when searching for minimum energy structures or during molecular simulation. The most important conditions for filtering are the maintenance of molecular chain integrity and the avoidance of steric clashes. These conditions can be seen as geometric constraints on a molecular model. In this article, we discuss how techniques issued from recent research in robotics can be applied to this filtering. Two complementary techniques are presented: one for conformational sampling and another for computing conformational changes satisfying such geometric constraints. The main interest of the proposed techniques is their application to the structural analysis of long protein loops. First experimental results demonstrate the efficacy of the approach for studying the mobility of loop 7 in amylosucrase from Neisseria polysaccharea. The supposed motions of this 17-residue loop would play an important role in the activity of this enzyme.     

A convexity relation for the energies of certain polymers of unit cells of different sizes

A simple rule in the form of total energy inequalities is proposed for special polymers of very large unit cells, in terms of some related polymers of small unit cells. If energy data can be calculated for the latter regular polymers, these energy values lead to energy constraints on the polymers of very large unit cells. The actual evaluation of these constraints involves only a simple inspection of the nuclear charges and elementary calculations.     

联吡啶构象异构的理论研究

采用HF/6-31G*方法,对6种联吡啶构造异构体进行了构象分析.之后采用B3LYP/6-311G**方法对处于势能面上的能量极小构象异构体进行全自由度几何优化和频率分析,并且寻找构象异构化过渡态.采用自洽反应场极化导体模型溶剂理论,探讨了水溶剂对优势构象异构体的几何结构和能量的影响.     

Variational second order density matrix study of F3-: importance of subspace constraints for size-consistency

Variational second order density matrix theory under "two-positivity" constraints tends to dissociate molecules into unphysical fractionally charged products with too low energies. We aim to construct a qualitatively correct potential energy surface for F(3)(-) by applying subspace energy constraints on mono- and diatomic subspaces of the molecular basis space. Monoatomic subspace constraints do not guarantee correct dissociation: the constraints are thus geometry dependent. Furthermore, the number of subspace constraints needed for correct dissociation does not grow linearly with the number of atoms. The subspace constraints do impose correct chemical properties in the dissociation limit and size-consistency, but the structure of the resulting second order density matrix method does not exactly correspond to a system of noninteracting units.     

Chemiluminescent reactions of manganese with fluorine: Influence of dynamics on product energy partitioning in vibration and rotation of MnF*(b,c)

Chemiluminescent exit channels of Mn+F2-->MnF*+F were investigated using the molecular beam technique in a beam-gas configuration with an array detector. Two uncongested regions, corresponding to MnF transitions c5Sigma+(b)-a5Sigma+(b) and b5Pi(i)(int)-a5Sigma+(b) were fit for vibrational and rotational populations, which were used to develop a microscopic reaction mechanism for these chemiluminescent exit channels. In both MnF* electronic states, significant vibrational excitation but little rotational excitation was found. Significant vibrational excitation has been attributed to early energy release as Mn loses an electron at long range to the lowest unoccupied molecular orbital on F2. The incipient bond is strengthened as backbonding from the F2- to Mn+ increases the covalent character of the intermediate. Finally, no strict geometric constraints are placed on the exit channel and hence there is no significant repulsive energy release into product rotation. Our proposed mechanism exhibits dynamic control in that the course of the reaction is determined by both geometric factors and dynamic factors.     

Inhibitors of prolyl endopeptidase: Characterization of the pharmacophoric pattern using conformational analysis and 3D-QSAR

Summary A structure-activity study has been carried out on several compounds known as inhibitors of the serine protease prolyl endopeptidase. Conformational analysis has been done using different molecular mechanics methods such as molecular dynamics, or a randomized conformational search method. The conformers obtained were classified using geometric and energetic criteria. A pattern recognition analysis was done in order to divide conformers according to families. The resulting dominant families, for all compounds investigated, showed very similar geometric features. Based on the lowest energy conformers obtained after randomized conformational analysis, a 3D-QSAR model was established using the CoMFA approach. The validity of this model was verified by prediciting correctly the activity of other molecules not used in the construction of this model.     

The Lagrange multiplier method for manipulating geometries. Implementation and applications in molecular mechanics

It is shown that a Lagrange multiplier method to constrain one or several internal coordinates, or averages and combinations of these, is easily implemented in a molecular mechanics computer program that uses Newton–Raphson (NR ) minimization. Results are given for constraints on nonbonded distances and torsion angles. When a potential energy surface is to be explored, it is much better to constrain the average of three torsion angles around a bond than to constrain a single torsion angle. Certain conversions can only be achieved when averages of torsion angles around different bonds are constrained. Combinations of constraints have been applied to evaluate differences between calculated and observed geometries and to obtain transition states for relatively large molecules from results for smaller molecules at relatively low costs. The efficieny of the combination of the Lagrange multiplier method and NR minimization in terms of computing time can be rated as good.     

可乐定分子构象异构和互变异构的理论研究

采用HF/6-31G*方法, 对氨基型和亚胺型可乐定中性分子以及质子化的可乐定分子进行了构象分析. 之后采用B3LYP/6-31G**方法对处于势能面上的能量极小构象异构体进行全自由度几何优化和频率分析. Onsager反应场溶剂模型用于水相的计算. 结果表明, 在气相和水相中可乐定中性分子主要以亚胺型存在, 这同已有实验结果一致. 进一步, 寻找构象异构化过渡态和氨基型亚胺型互变异构化过渡态, 探讨质子化和水溶剂化效应对异构化过程的几何结构和能量的影响. 为了考察氯苯的共轭效应对可乐定互变异构体稳定性的影响, 在B3LYP/6-31G**水平上, 研究了2-氨基-2-咪唑啉的互变异构化反应机理.     

乙烷脱氢制乙烯技术研究进展及趋势

在碳中和及全球能源供需版图调整的背景下,乙烯生产原料轻质化成为主流趋势。乙烷脱氢制乙烯技术具有低能耗、低碳排、流程短、收率高、成本低等优势,但目前工业上主要通过乙烷蒸汽裂解法生产乙烯,其他方法工业化生产相对不成熟。本文简述了近年来乙烷脱氢制乙烯技术(包括直接催化脱氢、O₂辅助氧化脱氢、CO₂辅助氧化脱氢、化学链氧化脱氢、催化膜反应器脱氢等)工艺及催化剂的研究现状,同时介绍了其他新兴工艺及催化剂。乙烷脱氢制乙烯技术现阶段面临的挑战不仅在于开发更高效的催化剂及更低能耗的技术,更需要突破乙烷脱氢热力学平衡的限制设计合适的反应路径,其中催化膜反应器脱氢、化学链氧化脱氢工艺都具有非常广阔的市场和工业化发展前景。     

A hierarchical construction scheme for accurate potential energy surface generation: an application to the F+H2 reaction

We present a hierarchical construction scheme for accurate ab initio potential energy surface generation. The scheme is based on the observation that when molecular configuration changes, the variation in the potential energy difference between different ab initio methods is much smaller than the variation for potential energy itself. This means that it is easier to numerically represent energy difference to achieve a desired accuracy. Because the computational cost for ab initio calculations increases very rapidly with the accuracy, one can gain substantial saving in computational time by constructing a high accurate potential energy surface as a sum of a low accurate surface based on extensive ab initio data points and an energy difference surface for high and low accuracy ab initio methods based on much fewer data points. The new scheme was applied to construct an accurate ground potential energy surface for the FH(2) system using the coupled-cluster method and a very large basis set. The constructed potential energy surface is found to be more accurate on describing the resonance states in the FH(2) and FHD systems than the existing surfaces.     

Constrained numerical gradients and composite gradients: Practical tools for geometry optimization and potential energy surface navigation

A method is proposed to easily reduce the number of energy evaluations required to compute numerical gradients when constraints are imposed on the system, especially in connection with rigid fragment optimization. The method is based on the separation of the coordinate space into a constrained and an unconstrained space, and the numerical differentiation is done exclusively in the unconstrained space. The decrease in the number of energy calculations can be very important if the system is significantly constrained. The performance of the method is tested on systems that can be considered as composed of several rigid groups or molecules, and the results show that the error with respect to conventional optimizations is of the order of the convergence criteria. Comparison with another method designed for rigid fragment optimization proves the present method to be competitive. The proposed method can also be applied to combine numerical and analytical gradients computed at different theory levels, allowing an unconstrained optimization with numerical differentiation restricted to the most significant degrees of freedom. This approach can be a practical alternative when analytical gradients are not available at the desired computational level and full numerical differentiation is not affordable. © 2015 Wiley Periodicals, Inc.