The Alkaline Hydrolysis of Sulfonate Esters: Challenges in Interpreting Experimental and Theoretical Data

Sulfonate ester hydrolysis has been the subject of recent debate, with experimental evidence interpreted in terms of both stepwise and concerted mechanisms. In particular, a recent study of the alkaline hydrolysis of a series of benzene arylsulfonates (Babtie et al., Org. Biomol. Chem. 10, 2012, 8095) presented a nonlinear Brønsted plot, which was explained in terms of a change from a stepwise mechanism involving a pentavalent intermediate for poorer leaving groups to a fully concerted mechanism for good leaving groups and supported by a theoretical study. In the present work, we have performed a detailed computational study of the hydrolysis of these compounds and find no computational evidence for a thermodynamically stable intermediate for any of these compounds. Additionally, we have extended the experimental data to include pyridine-3-yl benzene sulfonate and its N-oxide and N-methylpyridinium derivatives. Inclusion of these compounds converts the Brønsted plot to a moderately scattered but linear correlation and gives a very good Hammett correlation. These data suggest a concerted pathway for this reaction that proceeds via an early transition state with little bond cleavage to the leaving group, highlighting the care that needs to be taken with the interpretation of experimental and especially theoretical data

Des précurseurs organiques à la chiralité (simulations de processus élémentaires en environnement primitif)

À l heure actuelle, il est admis que l apparition de la vie sur Terre est liée à l émergence de l homochiralité des molécules bio-organiques. Le but de cette thèse est d étudier, dans le cadre de la panspermie, les conditions nécessaires à cette apparition. Cette étude, réalisée au moyen des méthodes de la chimie théorique, est centrée sur trois points clés de la problématique. À ce jour aucune molécule chirale n a été observée dans le MIS. La recherche de telles molécules constitue donc un point fondamental. En utilisant un critère de sélection basé sur le principe d énergie minimale, nous avons proposé une série de molécules chirales que nous considérons comme des cibles de choix pour une première observation dans le MIS. Une solution pour l obtention de milieux homochiraux consisterait à adsorber de manière énantiosélective un mélange racémique sur une surface chirale. Après avoir évalué les limites des modèles que nous proposons d utiliser pour notre modélisation d adsorption, nous avons recherché les divers points d adsorption existant sur la surface. Les résultats obtenus nous ont poussés à étudier la sélectivité de la surface dans sa globalité au moyen d une approche statistique de l adsorption. Enfin, on place communément la formation des acides aminés dans les glaces interstellaires. Se pose alors la question de la résistance de la chiralité des acides aminés au rayonnement interstellaire auquel ils sont soumis lors de leur voyage vers la Terre. À travers l exemple de l alanine nous évaluons le problème de la racémisation des acides aminés présents dans les glaces cométairesPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Computational Protein Engineering: Bridging the Gap between Rational Design and Laboratory Evolution

Enzymes are tremendously proficient catalysts, which can be used as extracellular catalysts for a whole host of processes, from chemical synthesis to the generation of novel biofuels. For them to be more amenable to the needs of biotechnology, however, it is often necessary to be able to manipulate their physico-chemical properties in an efficient and streamlined manner, and, ideally, to be able to train them to catalyze completely new reactions. Recent years have seen an explosion of interest in different approaches to achieve this, both in the laboratory, and in silico. There remains, however, a gap between current approaches to computational enzyme design, which have primarily focused on the early stages of the design process, and laboratory evolution, which is an extremely powerful tool for enzyme redesign, but will always be limited by the vastness of sequence space combined with the low frequency for desirable mutations. This review discusses different approaches towards computational enzyme design and demonstrates how combining newly developed screening approaches that can rapidly predict potential mutation “hotspots” with approaches that can quantitatively and reliably dissect the catalytic step can bridge the gap that currently exists between computational enzyme design and laboratory evolution studies

Computational Protein Engineering: Bridging the Gap between Rational Design and Laboratory Evolution

Enzymes are tremendously proficient catalysts, which can be used as extracellular catalysts for a whole host of processes, from chemical synthesis to the generation of novel biofuels. For them to be more amenable to the needs of biotechnology, however, it is often necessary to be able to manipulate their physico-chemical properties in an efficient and streamlined manner, and, ideally, to be able to train them to catalyze completely new reactions. Recent years have seen an explosion of interest in different approaches to achieve this, both in the laboratory, and in silico. There remains, however, a gap between current approaches to computational enzyme design, which have primarily focused on the early stages of the design process, and laboratory evolution, which is an extremely powerful tool for enzyme redesign, but will always be limited by the vastness of sequence space combined with the low frequency for desirable mutations. This review discusses different approaches towards computational enzyme design and demonstrates how combining newly developed screening approaches that can rapidly predict potential mutation “hotspots” with approaches that can quantitatively and reliably dissect the catalytic step can bridge the gap that currently exists between computational enzyme design and laboratory evolution studies