Unit:
Κατεύθυνση Βιοπληροφορική-Υπολογιστική ΒιολογίαLibrary of the School of Science
Supervisors info:
Εμμανουήλ Μικρός, Καθηγητής, Φαρμακευτική, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Original Title:
ΜΟΡΙΑΚΕΣ ΠΡΟΣΟΜΟΙΩΣΕΙΣ, ΜΕΛΕΤΗ ΔΙΑΜΕΜΒΡΑΝΙΚΩΝ ΥΠΟΔΟΧΕΩΝ
Translated title:
Molecular simulations, study of transmembrane receptors
Summary:
Members of the ubiquitous Nucleobase Ascorbate Transporter (NAT) family are H+ or Na+ symporters specific for the cellular uptake of either purines and pyrimidines or L-ascorbic acid. UapA is a prototypic, extensively studied at the genetic and functional level, fungal NAT showing high-affinity for xanthine and uric acid. Moreover, the crystal structure of UapA in complex with xanthine has been recently solved, allowing studies on the molecular mechanism that determines substrate selectivity using structure-based in silico prediction of binding affinities. Here, six xanthine analogues were selected to create accurate predictive models of the UapA-substrate interactions. Correlation models for experimentally determined Km and theoretical calculations of free energy ΔGo of xanthine analogues were created. In silico theoretical calculations and molecular simulations were made for predicting binding affinities using docking and molecular dynamics calculations (FEP, MMPBSA). As xanthine might acquire two tautomeric forms, based on the protonation of N7 or N9, both tautomers were utilized for all analogues. UapA was treated as monomer or dimer. The presence or absence of lipid bilayer in our calculations was considered, in order to produce the most accurate predicting model and investigate how the lipid bilayer might influence the binding affinities. Methods were evaluated in terms of their reliability in relation to the computational time needed. Finally, the results showed that more reliable results can be obtained from the study of a model in its monomeric form by the method of MM-PBSA, which is computationally faster than the rest studied.
Main subject category:
Science
Keywords:
fep, mmpbsa, xanthine, bioinformatics, dynamics, molecular
