Molecular modeling on reactions with lipases and related catalysts

Abstract: The first part of this thesis discusses theories and methodsin the field of molecular modeling. A brief introduction to thequantum chemistry methods and the forte field methods is given.Forte field parameterization is of central importante in theforte field methods and this Will be exemplified by aparameterization study of a copper(I)-olefin system complexedto bis-imino ligands.The setond part deals with acyl transfer reactions invacuum, in solution, and in a serine hydrolase.Ab initiocalculations were performed to investigate theproton transfer mechanisms in ester hydrolysis reactions inbasic, neutral and acidic media. The findings are compared withthose of studies made on model systems of serine hydrolasecatalyzed hydrolysis reactions. The transition stateapproximation used in this thesis for studying the serinehydrolase catalyzed acyl transfer reactions is discussed in thelight of the above studies.The third part discusses the chiral discriminations ofCundida anturcticu lipase B andCandida rugosalipase towards secondary alcohols anda-substituted alkanoic acids. Molecular modeling and kineticstudies were used to construct models that explain and predictthe enantioselectivity of these lipases. In these models theenantiomers bind in quite different orientations. Theenantiomeric ratios of several substrates were estimated bymeans of forte field calculations, based on these findings andthe use of various geometry- and energy-based subsets.Keywords:molecular modeling,ab inirio, ester hydrolysis, lipase, catalysis,enantioselectivity, serine hydrolase, parameterization, fortefield, bis-imino ligand, Cu(I)-olefin.