Bindings Of Peptides,Covalent Drugs And Oligosaccharides On Proteins Calculated Using Fragment Strategy

The interactions between protein and ligands,which include peptides,covalent drugs and oligosaccharides,have attracted extensive attention in recent years.They play an important role in the fields of medicine and food engineering,and make more and more researchers list them as the key research directions.The experimental method cost high and spend long.However,the rapid development of computer technology makes it possible and necessary to use computational methods to study and predict the conformation and energy of complex interactions between proteins and various molecules.In this paper,fragment strategy and a variety of other computational methods were used to study the docking of peptides on proteins,the interaction of Class A β-lactamases(Bla C)of Mycobacterium tuberculosis with carbapenems and the interaction of Flo1 p,a flocculent protein,with mannan oligosaccharides.The main contents are given as follow:(1)We developed a fragment-based docking protocol called DLPep Dock to predict protein-peptide interaction modes.Firstly,the long peptide is divided into fragments,which are docked in the peptide site,using a third-party small molecule docking tool.Then,the fragments are linked by coordinate transformation to reconstruct the whole peptide via a variety of linking schemes.After filtering unreasonable poses,the surviving conformations undergo clustering for extracting the representatives for further minimizing,MM/PBSA scoring and final ranking.A Shell script that can automatically complete the docking process is developed.Redocking tests were performed on peptide-protein complexes data sets with 6-12 amino acid residues.Compared with other docking methods,the results showed that DLPep Dock performed well.(2)Five new carbapenem compounds were designed by studying the binding conformation and energy of the Bla C of Mycobacterium tuberculosis and carbapenems.Their interactions include covalent and noncovalent parts.Based on the fact that the covalent energies of carbapenems and proteins are the same,we propose a hypothesis that the noncovalent interaction dominates the difference in the binding free energies of covalent ligands.The binding free energy calculated by MM/GBSA based on noncovalent interaction provides a threshold related to the experimental kinetic data.The R group of carbapenem molecules was fragmented,and new slow substrates were constructed according to the structural units of carbapenems or searched from ZINC15 database.Combining molecular docking with consensus scoring and molecular dynamics simulation with MM/GBSA binding free energy calculations,a computational protocol was developed.Five new carbapenems closely bound to Bla C were designed and identified from the view of molecular dynamics.(3)We studied the interaction between mannose oligosaccharides and Flo1 p,a yeast wildtype and mutant flocculating protein,and two mutants of Flo1 p,Q117N and Q117 R,were designed to enhance the binding strength.Molecular dynamics simulation and MM/GBSA binding free energy calculation were used to estimate the binding strength of mannan oligosaccharide chain in the gradual growth from monosaccharide to disaccharide,trisaccharide and tetrasaccharide.In the protein disaccharide stage,three possible mutation sites were found using alanine scanning mutation.Nine mutants were further analyzed and determined.Through further MD simulation and binding free energy calculation,the conformation and binding free energies were analyzed.Finally,it was determined that the binding free energy of two mutants Q117 N and Q117 R with mannan oligosaccharide were significantly stronger than those of wildtype protein.This study not only showed the structural pattern and binding affinity of two potential yeast cell flocculation regulatory mutants,but also provided a calculation example of estimating oligosaccharide binding strength using their terminal sugar residues.In this paper,the fragment strategy combined with various algorithms is successfully applied to study and predict the binding conformation and energy of peptides,covalent drugs and oligosaccharides on proteins,and the corresponding new structures are designed,which provides an effective and practical scheme for the calculation of these types of systems.