Pathway Optimization In Complex Configuration Spaces: Enzymes And Atom Clusters

Computational chemistry is one of the fastest growing areas of chemical orbiology research in the last decade. Through theoretical analysis and calculations to aspecific molecular system, one can accurately answer the basic chemical problems,for example, the structure stability and the reaction mechanism and so on. Today,computational chemistry has been widely used in materials, catalysis andbiochemistry research.In 21 century, life Science has become a comprehensive discipline based ontheoretical, experimental and computational sciences. In living organisms, tens ofthousands of biochemical reactions occur in one second. Such a wide variety ofcomplex biochemical reactions can be carried out successfully mainly relying on twoguarantees: one is energetic and the other is biocatalytic. The energetic one is ATP,and the biocatalytic one is enzyme. In most biological systems,enzyme is veryimportant because it can catalyze most biochemical processes and accelerate themetabolism of living organisms．The investigations on the catalytic mechanism ofenzymes focus on their high efficiency and the important intermediates along thereaction paths, which is a very important project in modern biology. Recently, greatprogresses have been achieved both in the three dimensional analytic techniques forprotein structures and in the field of gene engineering, especially in the field of thesite mutant techniques, which lead to the deep understandings of the enzymestructures. Based on the obtained information from experiments, the dynamicproperties and the reaction mechanism of the enzyme can be studied. However, thecorrelations between the enzymatic structure and its catalytic functions are not fullyclear,and what is the transition state and the intermediate structure? which amino acidresidue contributes to the catalysis? how to validate the right mechanism in a specificcatalytic process is also a challenging problem．In past few decades, computersimulation is playing an increasing role to study enzymatic mechanisms,whichcompensate the limitation of experimental and theoretical measures．In the first part of the dissertation, the catalytic mechanism of naturaltrans-sialidases from Trypanosoma Cruzi is investigated by QuantumMechanical/Molecular Mechanical simulation. The minimum energy path is exploredby NEB method. The changes of key interatomic distances along the minimum energypath are demonstrated. In the equilibrated structures of natural TcTs and substrate α-(2,3)-sialyl-lactose complex, it is seen that Tyr342/Glu230 and Asp59 are wellpositioned to act as acid/base catalysis similar to that of other retaining glycosidases.With the reaction proceeding, the distance of hydrogen bond between Tyr342 andGlu230 become shorter to facilitate the proton transfer and the nucleophilic attack.The conformational change in the sugar ring of the substrateα-(2,3)-sialyl-lactosefrom the distorted boat to the undistorted chair conformation accommodates thechange in relative position of Tyr342 and anomeric carbon of the substrate to form thecovalent bond. Transfer of sialic acid ontoβ-galactosyl acceptor in the second step isthen accomplished by essentially the reverse of above process. Our resultssubstantiate the role of Tyr342/Glu230 and Asp59 as the acid/base catalysis and areconsistent with a two-step double-displacement (ping-pong) mechanism proposedearlyIn second part, we located the structures of putative global minima for Morseclusters as a function of the range of the potential and the cluster size (with atomnumber 161≤N≤240) using the dynamic lattice searching method. Our work indicatesas the range of the potential is decreased, the structure of global minimum changesfrom disordered to icosahedral to decahedral to close-packed, and meanwhile the sizeeffect on structures becomes weaker. At the middle range of potential, the icosahedralstructures with Mackay overlayers are more predominant than those with anti-Mackayoverlayers. The conformational analysis of M200at differentρ0is given to get thefunnel information of the energy landscape. The energy sequences of global minimaat differentρ0are studied to find out the magic numbers, and the zero temperature"phase diagram"is given for an overall view of how the global minima depend uponN andρ0.