Insight Into The Interaction Mechanism Of Carbon Nanomaterials In Regard To PTP1B And Cellulase: A Molecular Dynamics Study

In recent years,nanomaterials have attracted extensive attention from scientists because of the special physicochemical property.The nanoparticle is able to efficiently transport in the biosome so that it has a lot of applications in the field of biological medicine and drug storage and delivery,which make it different and even superior from some traditional macroscopic matters in many fields.Meanwhile,the interdisciplinary science of nanomaterial with other subjects has become an emerging and hot issue in the scientific research.Among the numerous nanomaterials,the fullerene and its derivatives are mostly widely used in biomedicine on account of their special structure and chemical property.Many years ago,the fullerene derivatives were identified to exhibit potent inhibitory activity to HIV protease.And based on that research,a recent research found that several modified fullerene compounds are excellent inhibitors for protein tyrosine phosphatases(PTPs)despite of the unclear inhibitory mechanism.In this work,molecular optimization,molecular docking,molecular dynamics simulation and free energy calculation were integrated in this work in order to have insight into the binding mode and inhibitory mechanism of fullerene inhibitors to PTP1 B.It is interesting to find that the fullerene derivative can bind to the active site perfectly thanks to their comparable size with the active pocket.Besides,it is likely that fullerene derivatives can occupy the active site and hinder the binding of substrate by acting as competitive inhibitors.The negatively charged decorated-branches can form strong electrostatic interaction with residue Arg221 on P-loop,and Lys116 and Lys120 on the recognition loop,which may be the main force for fullerene derivatives entering into the active pocket,while the Van der Waals contribution from nonpolar residues to the fullerene C60 cage is another reason for the stability of fullerene in the active site.Moreover,the binding of fullerene inhibitors will lead to the rotation of WPD loop,and the catalytic acid Asp181 get away from the active site,which also have positive effect on the inhibitory activity.The study of inhibitory mechanism of fullerene derivatives to PTP1 B can provide theoretical guide for the design and improvement of novel and potent inhibitors.In addition,we studied immobilization process cellulase Cel48 F on graphenes,and the change of catalytic activity influenced by the immobilization.It is found that apart from Glu55 and Asp230,residue Glu44 can also significantly affect the catalytic activity by retaining the conformation of substrate and participating in the release process of product.Subsequently,the steered molecular dynamics simulation was carried out to understand the product dissociation.The result indicates that the hydrogen bonding rearrangement caused by Clu44,Glu55,Asp494 and Trp611 can effectively reduce the sliding energy barrier of product and thus accelerate its release process.When the product moves to the exit of protein,the solvent plays the prominent role in the product dissociation.Based on the study of Cel48 F,we further investigate the immobilization process of cellulase on graphenes,and find that the protein gets close to the graphene by ?-? interactions and staking interactions of some nonpolar residues.To sum up,the interaction mechanism of nanomaterials in biological systems studied by molecular dynamics simulation can provide theoretical guide for the biological application as well as improvement of carbon nanomaterials.