Studying On The Interaction Of FTO Protein With Small Molecules By Spectroscopy And Molecular Docking

Studying the interaction between proteins and small molecules is very important.On the one hand,it can help us explore the effects of small molecules on protein structure and function;on the other hand,it can help us understand the distribution,metabolism and other information of small molecules in the body,provide resources for the design and development of new drugs.The fat mass and obesity associated(FTO)gene is the first obesity related gene and highly expressed in the hypothalamus,skeletal muscle,fat and other huaman tissues,it can control obesity by controlling food intake and energy consumption.The FTO gene product is a nucleic acid demethylase,and its primary role in mammals is to regulate energy balance.So,studying the interaction between FTO and small molecular is of great importance for the development of obesity-related drugs.Fluorescence and UV-Vis absorption spectroscopy have many advantages,such as simple operation,high sensitivity and fast analysis speed.At the same time,it can provide the mechanism,the binding constants and the type of forces of the interaction between small molecules and proteins.Molecular modeling technique can vividly show the result of the interaction between small molecules and proteins.Therefore,the interactions between six different types of small molecules and FTO were studied by spectral analysis and molecular docking technique.This paper includes the following seven parts:The first chapter summarized the significance of the interaction and gave a brief introduction about FTO.The common research methods and the research contents of interaction are summarized.In the second chapter,we studied the interaction between FTO and three flavonoids(quercetin,apigenin and naringenin).The results of spectroscopic studies indicate that three flavonoids can quench the intrinsic fluorescence of FTO through static quenching.Hydrophobic and electrostatic interaction forces might play a major role in the interaction of FTO with quercetin,but the acting forces are mainly hydrophobic interaction and hydrogen bonds between FTO and apigenin(or naringenin).The binding ability of quercetin to FTO is the strongest among the threecompounds,which may be related to the presence of more hydroxyl groups in quercetin.The polar of microenvironment surrounded tryptophan residues enhanced after addition of naringenin.In the third chapter,the interactions between FTO and six quinazolinone derivatives were studied under mimic physiological condition.Results showed that Q1,Q2,Q3 and Q4 could quench the endogenous fluorescence of FTO through static quenching process,whereas Q5 and Q6 could not.We judged that may be related to the substituents in the molecular structure.The binding ability is related to the steric hindrance of derivatives.Hydrophobic interactions played a major role in the binding of four quinazoline derivatives to FTO.The polar of microenvironment surrounded tyrptophan residues changed after addition of Q2 and Q4.In the fourth chapter,we studied the interaction between FTO and four Taiwaniaquinones(two groups of isomers)in mimic physiological condition.The results showed that four Taiwaniaquinones could quench the fluorescence of FTO through static quenching mechanism.The binding ability between two isomers and FTO was related to the conjugation system in the molecules.The combination between four Taiwaniaquinones and FTO could change the conformation of FTO.Moreover,the polar of microenvironment surrounding tryptophan residues changed after the combination of FTO with T1.Hydrophobic interaction might play a major role in the binding processes.In the fifth chapter,we studied the interaction between FTO and four2-aminochromones.The results showed that four 2-aminochromones could quench the fluorescence of FTO through static quenching mechanism.The steric hindrance is the main factor affecting the binding strength of the compounds with FTO.Hydrophobic interactions played a major role in the binding processes.There is no apparent change in the polar of microenvironment surrounding where tyrosine and tryptophan residues.In the sixth chapter,we studied the interaction between FTO and three nucleoside analogues.The results indicated that three nucleoside analogues could quench the fluorescence of FTO through static quenching mechanism.Hydrophobic interaction forces might play a major role in the interaction between FTO and N1,vander Waals and hydrogen bonds might be the major forces in the interaction of FTO with N2,and the acting force was mainly hydrogen bonds in the interaction between FTO and N3.The quenching and binding ability of N1 was greater than the other two nucleoside analogues,which may be related to the non-polar benzene ring in N1.The results of synchronous fluorescence indicated that N2 and N3 could cause the polarity of tryptophan microenvironment to change.The seventh chapter studied the interaction of diethylstilbestrol(DES)with FTO.DES could quench the fluorescence of FTO protein through static quenching mechanism.Hydrophobic interactions played a major role in the formation process complex.There is no apparent change in the polar of microenvironment surrounding where tyrosine and tryptophan residues.