Molecular Dynamics Simulation On The Orientation Of Like-charged Protein On The Charged Surface

Protein aggregation during protein refolding is a fundamental issue in theproduction of recombinant therapeutic proteins. Like-charged ion-exchange resin hasbeen found efficient to suppress the aggregation of folding intermediates, leading to asignificant increase of native protein recovery. It has been proposed that the workingmechanism of the like-charged resin is related to the oriented alignment of proteinmolecules near the charged surface induced by charge repulsion. This orientedalignment is supposed to inhibit protein aggregation. However, it is difficult to verifythe proposed mechanism using experimental approaches.Molecular dynamics (MD) simulation is a powerful tool which can offer clearmicroscopic information in a direct manner. It can also provide the macroscopicinformation of the simulation system. It is useful and has been widely used tounderstand protein conformational transition at molecular level.In the present study, the distribution of protein molecules near a like-chargedsurface has been investigated using molecular dynamics (MD) simulation. Bothcoarse-grained (CG) model and all-atom (AA) model have been utilized to provide acomprehensive description of the microscopic process. The effect of electrostaticrepulsion strength has been examined by adjusting the charge number of protein andsurface. It is found that like-charged protein is excluded from the charged surface withsufficient electrostatic repulsion. During this process, adjustment of proteinorientation is observed to form the oriented alignment, where the dipole of the proteinis perpendicular to the charged surface. Better oriented alignment is observed withstronger electrostatic repulsion, but with larger disturbance on the proteinconformation, indicated by more unfolded protein. Moreover, very strong repulsioncauses serious unfolding of protein molecules and then serious aggregation. Therefore,appropriate electrostatic repulsion strength is necessary to get the maximum nativeyield.