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Molecular modeling and 3D QSAR approach to molecular recognition

Recognition between (bio)(macro)molecules is crucial for all aspects of life. Although the molecular pathways can be complicated and network structured many of the recognition phenomena are based on single molecule interactions. Due to exponentially expanding number of known 3D (three dimensional) structures of (for biomedical research) target macromolecules it is important to develop accurate and efficient computer methods that will use the full information contained therein. We developed a method based on molecular modelling and 3D QSAR (Quantitative Structure Activity Relationship). Outline of the method and results obtained for two different systems will be presented. a) Lipase Study was performed in order to derive a model for enantioselectivity of bacterial lipase, namely lipase from of Burkholderia Cepacia (BCL), towards primary and secondary alcohols. The most probable conformers of the substrate tetrahedral intermediates were elucidated and their interactions with the amino acid residues at the binding pocket(s) were calculated. The free energy difference between TIs of two enantiomers was approximated by the residue-based sum of potential energy differences and the solvent accessible surface area differences. The results obtained can be used to predict enzyme enantioselectivity in a substrate transformation as well as to plan point mutations of the enzyme to achieve high enantioselectivity in the enzyme catalysed transformation of specific substrates. b) Nuclear receptor DNA binding To identify the major determinants of the DNA binding specificity of nuclear transcription factors, two sets of glucocorticoid receptor transcription factor mutants binding to different panlindromic elements were studied. It was found that the parameters important for binding, non-specific and specific, of nuclear transcription factors to DNA are similar in both sets of complexes. The dominating parameters are solvation free energy of the central (mutated) bases of a hexameric half site and the electrostatic interaction between the central nucleotides and the mutated residues (residues from so called P-box) as well as some more distant charged amino acid residues.

QSAR; COMBINE; Protein-DNA; Lipase

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