Studies On Two Human Protein-Ligand Binding Mechanisms Based On Binding Free Energy

Proteins play various roles in human life activities,and the study of their structure and function is of great significance to promoting human health.The rapid development of theoretical computing has facilitated the study of current protein systems.In this paper,aiming at the complex system problems closely related to human health faced by the field of food science,a systematic study was conducted on the effects of angiotensin-converting enzyme(ACE)and inhibitory peptides,sweet taste receptors(Taste Receptor Type Member 2/3,T1R2/T1R3)and sweeteners.The complexity of the ACE system lies in its thousands of ligands.ACE plays an important role in blood pressure regulation,and overexpression of this protein can lead to hypertension.Most of the current hypertension drugs have different degrees of side effects,and food-derived ACE inhibitory peptides have attracted much attention due to their wide sources and good safety.However,there is currently no systematic and effective method to screen ACE inhibitory peptides,and there is a lack of knowledge about the characteristics of inhibitory peptides and related mechanisms of action.Therefore,this paper firstly and systematically completed the evaluation of the ACE inhibitory effect of 160,000 tetrapeptides through molecular docking.Through statistical analysis,it was found that the tetrapeptide containing W,Y,F,H or R residues may have better inhibitory effect.The binding free energy calculation and IC₅₀experiments of the first 10 and the last 2 ACE-tetrapeptide complexes verified this conclusion,and it was found that the best inhibitory effect was YYWK(IC₅₀=19.98±8.19?M).This provides direction for the subsequent screening of ACE inhibitory peptides.The complexity of the T1R2/T1R3 system lies in the fact that the receptor is a membrane protein,the system is large and complex,and the structure is not available.T1R2 can bind most sweeteners.Understanding the mechanism of action of sweet receptors is important for designing new healthy sweeteners.However,little is known about the structures and recognition mechanisms of this receptor and related proteins.In this paper,the structure was constructed by homology modeling,and 28 major sweeteners were evaluated by molecular docking.8 typical sweeteners were selected to construct sweetener-T1R2-membrane systems,and the interaction between receptors and sweeteners was further analyzed.Computational results show that low-intensity natural sweeteners,fructose and xylitol,are released from the binding pocket at?30 ns with a shift>50?;while artificial sweeteners,neotame and advantame,bind stably to the receptor with a shift within 5?.Van der Waals forces plays a significant role in high-intensity sweetener systems.These results provide a deeper understanding of the mechanism of action of sweeteners and provide new directions for sweetener design.