中文摘要：

抑制蛋白质聚集是应用基因重组技术生产药用蛋白质过程中的关键.实验研究发现与蛋白质带同种电荷的离子交换介质能够通过静电排斥作用有效抑制蛋白质折叠中间体的聚集.但其微观细节尚不明晰,且利用现有实验技术很难直接阐释.分子动力学模拟是研究微观过程的有力工具.因此,本文构建了静电排斥表面模型以模拟同电荷离子交换介质,采用分子动力学模拟和全原子模型,研究溶菌酶在静电排斥表面上的空间取向及其变化过程,并考察表面所带电荷数的影响规律.结果表明,溶菌酶受到表面的静电排斥作用而远离.在此过程中,溶菌酶逐渐＂站立＂,形成其偶极和表面相站立垂直的空间取向.而当蛋白质远离表面时,由于静电排斥作用衰减,形成＂站立＂取向的趋势减弱.同时,研究发现静电排斥表面所带电荷数增加有利于蛋白质形成＂站立＂取向.本文的模拟结果从微观揭示蛋白质在静电排斥表面上的空间取向及其影响因素,将有助于推动蛋白质在荷电表面折叠和分子相互作用研究.

英文摘要：

Inhibition of protein aggregation during protein refolding is a fundamental issue in the production of recombinant therapeutic proteins.It has recently been experimentally found that like-charged ion-exchange resin can suppress the aggregation of folding intermediates through electrostatic repulsion.However,the microscopic understanding of this process is far from adequate,and it is difficult to examine the microscopic process using experimental approaches.Molecular dynamics（MD） simulation is a powerful tool which can provide clear microscopic information in a direct manner.Therefore,in the present study,a model of an electrostatically repulsive surface is constructed to simulate the like-charged ion-exchange resin.The distribution of lysozyme molecules near the surface is then investigated using MD simulation with all-atom（AA） models and the effect of the charge number of the surface is examined.It is found that the protein is excluded from the surface by electrostatic repulsion.During this process,the protein molecule becomes standing,where the dipole of the protein is perpendicular to the surface.When the protein moves far from the surface,diminished oriented alignment is observed due to the decreased electrostatic repulsion from the surface.It is also found that better oriented alignment on the surface occurs with higher charge number.The simulation results thus provide microscopic information about the alignment of protein molecules near an electrostatically repulsive surface,and are expected to be helpful for investigation of protein refolding on charged surfaces and the molecular interactions involved.