Development and application of conformational methodologies: eliciting enthalpic global minima and reaction pathways

2014 Fall.The information granted by assembling the global minimum and low-enthalpy population of a chemical species or ensemble can be utilized to great effect across all fields of chemistry. With this population, otherwise impossible tasks including (but not limited to) reaction pathway characterization, protein folding, protein-ligand docking, and constructing the entropy to characterize free energy surfaces becomes a reasonable undertaking. For very small systems (single molecule with 1-3 torsions) generating the low-enthalpy population is a trivial task. However as the system grows, the task exponentially increases in difficulty. This dissertation will detail the two sides of this problem, generating the low-energy population of larger and more complex species and then utilizing those populations to garner a greater understanding of their systems. The first discussion describes a new model, Surface Editing Molecular Dynamics (SEMD), which aids in accelerating conformational searching by removing minima from the potential energy surface by adding Gaussian functions. Accompanying this new method are a multitude of new tools that can be utilized to aid in molecular dynamics simulations. The first of these tools, named CHILL, performs a projection of unproductive degrees of freedom from the molecular dynamics velocity to smooth atomic motions without artificially constraining those degrees of freedom. Another tool, Conjugate Velocity Molecular Dynamics (CVMD), rigorously generates a list of productive velocities via the biorthogonalization of local modes with a vector representation of previously explored conformational minima. In addition to these tools, a new description of distance in torsional space was developed to provide a robust means of conformational uniqueness. With each of these tools working in concert, the global minimum and associated low-enthalpy population of conformations have been obtained for various benchmark species. The second section discusses the application of conformational searching and the subsequent electronic structure calculations to characterize the reaction pathway for the ruthenium tris(2,2'-bipyridine) photocatalyzed [2+2] cycloaddition of aromatically substituted bis(enones). The APFD hybrid density functional is used along with a 6-311+g* basis and a PCM solvent model. The reaction is computed to proceed through a rate-limited formation of a cyclopentyl intermediate. Lithium tetrafluoroborate is found to facilitate initial bis(enone) reduction as well as final product distribution. In addition, aromatic substituents are found to impact both initial reduction and final product distribution

Globale Optimierungsmethoden, basierend auf Tabu-Suche

This work encompasses three parts. The first part provides a concise review of the most prominent metaheuristic concepts currently available and gives essential preliminaries together with definition of the combinatorial optimization problems. It substantiates the choice of the investigation direction and basis idea of the developed methods. In the second part the new nonlinear global optimization routines based on the TS strategy are described. The new approaches are the Gradient Tabu Search (GTS), the Gradient Only Tabu Search (GOTS), and the Tabu Search with Powell’s Algorithm (TSPA). In the last part of the work the GOTS is applied for such chemical optimization problems. The chapter provides a systematic approach how the variables are chosen and the adjustable parameters are set. As test cases the global minimum energy conformation of some amino acids, of two angiotensin converting enzyme (ACE) inhibitors, of 2-acetoxy-N,N,N-trimethylethanaminium, and of a HIV-1 protease inhibitor is determined.Die Arbeit umfasst drei Kapitel. Das erste Kapitel stellt eine kurze Zusammenfassung über die bekanntesten, zurzeit verwendeten Metaheuristischen-Konzepte dar und gibt notwendige Einleitungen zusammen mit der Definition der kombinatorischen Optimierungsprobleme. Das Kapitel begründet die Wahl des Tabu-Ansatzes und diskutiert die Basisideen der entwickelten Methoden. Im zweiten Kapitel werden die neuen entwickelten, nichtlinearen Optimierungsroutinen beschrieben, die auf Tabu-Suchstrategien beruhen. Die neuen Algorithmen sind Gradient Tabu Search (GTS), Gradient Only Tabu Search (GOTS) und Tabu Search with Powell’s Algorithm (TSPA). Das letzte Kapitel der Arbeit beschreibt die Anwendung der GOTS Methode auf dieses Problem. Diskutiert werden die Auswahl der Variablen und die Einstellung der justierbaren Parameter. Die Effizienz der GOTS Methode wird an Hand einiger Aminosäuren, zwei Angiotensin-Derivaten (ACE-Hemmer), des Acetylcholin und eines HIV-1-Protease-Hemmstoff gezeigt