Biomechanical Response Of Cadherin Dimerization By All-Atom Molecular Dynamics Simulation

The human body is constructed by macromolecules,cells,tissues and organs hierarchically.Therefore,the macro biological functionality of the human body is ultimately attributed to the biomechanical response of macromolecules in nano-microscale.It is of great significance to study the biomechanical response of biomacromolecules in order to explore the relevant pathological and physiological phenomena.Cadherin,a kind of cell adhesion molecule,plays a vital role in maintaining the morphogenesis and integrity of organisms.It induces a significant impact on the body if the adhesion system is dysfunctional,such as cancer invasion and metastasis,skin diseases and cardiomyopathy.Meanwhile,cadherin plays a crucial role in the process of cell migration caused by epithelial mesenchymal cell transformation,leading to tumorigenesis eventually.There are three subtypes of cadherin.Even though they have similar crystal structure,their biomechanical response to external loads and the interaction between each other are various.This dissertation aims to: 1)characterize biomechanical properties and dynamic response of type I and type II cadherin dimers by all-atom molecular dynamics simulation;2)analyze the binding energy of cadherin monomers during interaction.The specific research contents are as follows:First of all,based on the pathogenesis of cancer induced by cadherin dysfunction,three kinds of homologous cadherin dimer models based on human genome protein library and atomic force probe models were constructed.An atomic force microscope probe indented on E-cadherin,N-cadherin and VE-cadherin under physiological environment was stimulated based on all-atom molecular dynamics method using software GROMACS2019.The variation in mechanical responses among the three types of cadherin dimers were revealed in terms of molecular root mean square deviation,adhesion,stiffness and elastic modulus.Secondly,six groups of cadherin interaction including both homologous and heterologous were established through molecular docking in order to simulate cell migration in the human body.The interactions were simulated by molecular dynamics under the condition of physiological microenvironment.The binding properties of both homologous and heterologous were revealed in terms of radius of gyration,number of hydrogen bonds,and RMSD,in order to illustrate the differences in the stability,affinity,and binding residues.The significance of this dissertation is that,1)Mechanical response of type I and type II cadherin dimers were revealed by studying the nano-indentation of atomic force microscope probe on E-cadherin,N-cadherin and VE cadherin under the condition of physiological microenvironment;2)The interaction between homologous and heterodimer was simulated by molecular dynamics,which revealed the reasons for the difference of mechanical properties of different cadherin monomers during the binding process,and constructed a bridge for the study of mechanical properties characterization of cadherin dimer-cell-organism.