Protein-Ligand Etkileşimlerinin Kuantum Mekaniksel/Moleküler Mekaniksel Simülasyon Teknikleriyle İncelenmesi

Abstract

Research of metal-ion dependant biomolecular systems with in silico quantum mechanics/molecular mechanics (QM/MM) approaches is the main purpose of this study. Conformational pathway of natural substrates during reaction predicted by experimental work on enzyme-inhibitor complexes is also aimed to be found. To achieve, structure of an enzyme which is Calcium (Ca2+)-dependent alpha-mannosidase present in a human gut symbiont bound to two inhibitors and a natural substrate alpha-1,2-Mannobiose has been investigated using Molecular Dynamics (MD) and Metadynamics (MTD) simulation techniques. In the structure involving natural substrate, observed conformations of the sugar ring using metadynamics on Cremer-Pople puckering coordinates are coherent with the experimental data for the reactant and the transitional state. To additionally determine activation and reaction energy, role of metal ion and conformational pathway followed by natural substrate, a series of QM/MM MTD computations with different parameters were initiated. Evaluated data obtained through methods and approaches used in this study potentially can help to expand of our knowledge of catalytic mechanisms of glycosidases and to design diagnostic and therapeutic drugs for lysosomal storage diseases like alpha-mannosidosis.