Automated Identification and Classification of Stereochemistry: Chirality and Double Bond Stereoisomerism

Stereoisomers have the same molecular formula and the same atom connectivity and their existence can be related to the presence of different three-dimensional arrangements. Stereoisomerism is of great importance in many different fields since the molecular properties and biological effects of the stereoisomers are often significantly different. Most drugs for example, are often composed of a single stereoisomer of a compound, and while one of them may have therapeutic effects on the body, another may be toxic. A challenging task is the automatic detection of stereoisomers using line input specifications such as SMILES or InChI since it requires information about group theory (to distinguish stereoisomers using mathematical information about its symmetry), topology and geometry of the molecule. There are several software packages that include modules to handle stereochemistry, especially the ones to name a chemical structure and/or view, edit and generate chemical structure diagrams. However, there is a lack of software capable of automatically analyzing a molecule represented as a graph and generate a classification of the type of isomerism present in a given atom or bond. Considering the importance of stereoisomerism when comparing chemical structures, this report describes a computer program for analyzing and processing steric information contained in a chemical structure represented as a molecular graph and providing as output a binary classification of the isomer type based on the recommended conventions. Due to the complexity of the underlying issue, specification of stereochemical information is currently limited to explicit stereochemistry and to the two most common types of stereochemistry caused by asymmetry around carbon atoms: chiral atom and double bond. A Webtool to automatically identify and classify stereochemistry is available at http://nams.lasige.di.fc.ul.pt/tools.ph

Enumerating molecules.

This report is a comprehensive review of the field of molecular enumeration from early isomer counting theories to evolutionary algorithms that design molecules in silico. The core of the review is a detail account on how molecules are counted, enumerated, and sampled. The practical applications of molecular enumeration are also reviewed for chemical information, structure elucidation, molecular design, and combinatorial library design purposes. This review is to appear as a chapter in Reviews in Computational Chemistry volume 21 edited by Kenny B. Lipkowitz

Development of efficient open-source chemical graph generators

In chemistry, one of the crucial problems has been the structure identification of molecules, whose chemical composition is unknown. This research topic has impacts on various fields such as natural product and drug discovery studies. For the efficient and the fast identification process, computer assisted structure elucidation (CASE) toolkits has been developed. These tools utilise spectral data of unknown molecules as the input to determine their structure. The effectiveness of these software primarily depends on how well the structure generators perform. The basic input for these generators is the molecular formula of the unknown molecule to generate its unique list of isomers. In cheminformatics, there has been several software for the structure generation, especially, MOLGEN was considered as the de-facto gold standard in the field due to its speed and efficiency. However, it is a commercial tool and there was the need of an efficient open-source structure generators, in other words, chemical graph generators. To fulfil this need, the development of efficient open-source chemical graph generators was aimed for this PhD study, and the aim was succeeded by the development of two software, namely, MAYGEN and surge. First MAYGEN was developed as an alternative to MOLGEN. It was benchmarked against MOLGEN and was just around 3 times slower than MOLGEN. Following MAYGEN, another software, surge, was developed as an open-source chemical graph generator. It was benchmarked against MOLGEN for randomly chosen natural products' molecular formulae. Based on the results, surge is approximately 100 times faster than MOLGEN, which made it the state-of-art in the field

The octet rule in chemical space: Generating virtual molecules

We present a generator of virtual molecules that selects valid chemistry on the basis of the octet rule. Also, we introduce a mesomer group key that allows a fast detection of duplicates in the generated structures. Compared to existing approaches, our model is simpler and faster, generates new chemistry and avoids invalid chemistry. Its versatility is illustrated by the correct generation of molecules containing third-row elements and a surprisingly adept handling of complex boron chemistry. Without any empirical parameters, our model is designed to be valid also in unexplored regions of chemical space. One first unexpected finding is the high prevalence of dipolar structures among generated molecules.Comment: 24 pages, 10 figure

Kinetic model construction using chemoinformatics

Kinetic models of chemical processes not only provide an alternative to costly experiments; they also have the potential to accelerate the pace of innovation in developing new chemical processes or in improving existing ones. Kinetic models are most powerful when they reflect the underlying chemistry by incorporating elementary pathways between individual molecules. The downside of this high level of detail is that the complexity and size of the models also steadily increase, such that the models eventually become too difficult to be manually constructed. Instead, computers are programmed to automate the construction of these models, and make use of graph theory to translate chemical entities such as molecules and reactions into computer-understandable representations. This work studies the use of automated methods to construct kinetic models. More particularly, the need to account for the three-dimensional arrangement of atoms in molecules and reactions of kinetic models is investigated and illustrated by two case studies. First of all, the thermal rearrangement of two monoterpenoids, cis- and trans-2-pinanol, is studied. A kinetic model that accounts for the differences in reactivity and selectivity of both pinanol diastereomers is proposed. Secondly, a kinetic model for the pyrolysis of the fuel “JP-10” is constructed and highlights the use of state-of-the-art techniques for the automated estimation of thermochemistry of polycyclic molecules. A new code is developed for the automated construction of kinetic models and takes advantage of the advances made in the field of chemo-informatics to tackle fundamental issues of previous approaches. Novel algorithms are developed for three important aspects of automated construction of kinetic models: the estimation of symmetry of molecules and reactions, the incorporation of stereochemistry in kinetic models, and the estimation of thermochemical and kinetic data using scalable structure-property methods. Finally, the application of the code is illustrated by the automated construction of a kinetic model for alkylsulfide pyrolysis

Computational Study of Proton Ordering in Ice and Icelike Systems

Recently, there has been a lot of interest to computationally study ice and icelike systems. Simulating such structures, using ab initio methods require atomic level models. However, creating adequate models for ice is challenging, as there are a huge number of isomers for any ice formation. Two factors contribute to the number of isomers: (i) the positions of oxygens that give rise to various crystal structures, and (ii) the possibilities for hydrogen atom positions for each crystal structure. The second factor means that many nearly degenerate ``proton configurations'' exist for ice. Consequently, large entropy can be observed for ice at normal temperatures. However, because of the large energetic barriers between different proton configurations, 'residual' entropy can be measured even at 0 K. In this thesis, the proton configurational disorder in ice and icelike systems is studied computationally using ab initio methods. In addition, a computer program is developed to aid in the generation and analysis of proton configurations. The systems discussed in the four articles of this thesis are the normal ice (ice Ih), protonated and neutral ice clusters, and icelike systems on surfaces. In the case of ice Ih, the ordering to the lowest energy configuration (ice XI) and the claimed ferroelectricity of this configuration are studied using ice films with and without natrium hydroxide dopants. Calculations with ice films on platinum surfaces were also performed. According to my results, ice XI is not ferroelectric, although NaOH and the Pt(111) substrate are observed to cause some ordering. In the context of ice clusters, phenomena behind the abundance of the 'magic number clusters', observed in experiments, are studied. The results indicate that the protonated cluster energetics are dominated by the local geometry of the H9O4+ Eigen complex, which prefers a near-planar orientation. In addition, the number of hydrogen bonds in a cluster is seen to affect the energetics. However, a proton configurational analysis indicates that the cluster energetics are also affected by the entropy caused by the number of proton configurations. The icelike systems containing less than four-fold coordinated water molecules are studied, and relationships are established between 'hydrogen bond connectivity parameters' and proton configuration energetics.Viime aikona jään ja jäänkaltaisten systeemien laskennallinen tutkiminen on yleistynyt merkittävästi. Kuitenkin jäärakenteiden simuloiminen ab initio -menetelmiä käyttäen on haastavaa, sillä sopivien teoreettisten mallien löytäminen on hankalaa. Jäällä on useita happiatomihiloja, joille jokaiselle on olemassa valtava määrä erilaisia vaihtoehtoja järjestää vetyatomit happiatomien väliin. Näin jokaiselle pienellekin jään kaltaiselle rakenteelle on olemassa hyvin monia lähes energeettisesti identtisiä ``protonikonfiguraatioita'', joten merkittävää entropiaa on havaittavissa normaaleissa lämpötiloissa. Protonikonfiguraatioiden välillä on merkittäviä energiavalleja, jotka estävät muutoksen yhdestä muodosta toiseen. Entropiaa havaitaankin myös 0 K:n lämpötiloissa. Väitöskirjassa tutkitaan protonikonfiguraatioiden aiheuttamaa epäjärjestystä jäässä ja jäänkaltaisissa systeemeissä käyttäen ab initio -menetelmiä. Lisäksi esitellään tietokoneohjelma, joka on kehitetty generoimaan ja analysoimaan protonikonfiguraatioita. Väitökseen liittyvissä artikkeleissa käsitellään seuraavia rakenteita: tavanomaista jäätä (jää Ih), positiivisesti varattuja ja neutraaleja jääryppäitä, sekä jäänkaltaisia systeemejä pinnoilla. Väitöskirjan tavanomaiseen jäähän liittyvässä artikkelissa käsitellään järjestymistä alimman energian protonikonfiguraatioon, joka tunnetaan nimellä jää XI. Erityisesti artikkeli argumentoi kyseisen muodon väitettyä ferroelektrisyyttä vastaan. Ab initio -laskujen perusteella, jonkinlaista jään dipolien järjestymistä voidaan havaita natriumhydroksidiliuoksesta valmistetussa jäässä, kuten myös jääfilmeissä, jotka muodostuvat platinapinnan päälle. Jääryppäisiin liittyen väitöskirjassa tarkastellaan ilmiöitä, jotka aiheuttavat tietyn kokoisten positiivisesti varattujen jääryppäiden tavanomaisesta poikkeavan runsauden. Saadut tulokset viittaavat siihen, että ryppäissä H9O4+ Eigen-kompleksin paikallinen geometria on suurin energiaan vaikuttava tekijä. Tämä kompleksi on vähiten jännittyneessä tilassa ryppäissä, joissa se on tasomaisessa ympäristössä. Lisäksi ryppäiden energetiikkaan vaikuttaa niissä olevien vetysidosten määrä. Laskujen perusteella havaittiin, että ryppäiden protonikonfiguraatioiden määrä on merkittävä tekijä siinä, mikä ryväsmuotoa havaitaan eniten kokeellisissa tutkimuksissa. Väitöskirjaan liittyvässä tutkimuksessa etsitään myös tilastollista riippuvuutta erilaisten jään kaltaisten systeemien sitoutumisparametrien ja elektronisen energian välille

An extensive English language bibliography on graph theory and its applications

Bibliography on graph theory and its application