基于多步限制势计算蛋白质在固液界面吸附自由能的方法研究

Adsorption free energy is the key thermodynamic parameter that characterizes the recognition ability and affinity between inorganic materials and proteins in solution. The measurement of this parameter has important applications in the fields of chemical engineering and materials etc., for example, in the surface construction of protein-antifouling membranes/reactor and biomimetic material preparation. However, since the thermodynamic process of protein adsorption on the solid surface is very complicated, involving many degrees of freedoms of the system, currently there exists no an elegant solution to calculate protein adsorption free energy on surface. In this work, we propose a general methodology on the basis of potential of mean force, in which a thermodynamic cycle with multiple restraining potentials is constructed to reduce the degrees of freedom, thus increasing the conformational sampling efficiency. Through this multistage protocol, the protein adsorption free energy can be calculated in the rapid and accurate way. With the aid of free energy calculation, we further provide the atomic-level understanding of the mechanism on the peptide/protein specific adsorption and conformational changes. It is believed that the present study not only provides computational protocols of biomolecule adsorption on the surface, which are applicable to large proteins, but also offer a possible way for quantitatively evaluating the performance of the new-designed biomaterials and biomolecules.

吸附自由能是衡量溶液中蛋白质分子与固体材料表面之间选择识别能力以及相互作用强度的重要热力学量，其计算与测定在化学化工和材料等领域有着重要意义，例如抗蛋白质污染膜/反应器表面的构建以及仿生材料的制备等。然而，由于蛋白质在固体表面上吸附热力学过程比较复杂，分子体系中存在大量的自由度，使吸附自由能难以计算。本项目提出基于路径积分自由能计算方法，通过添加多步限制势在蛋白质远离固体表面自由状态以及界面吸附平衡状态之间建立严谨的热力学循环，以减少体系的构型自由度，从而降低模拟计算中构型样本的取样难度和提高蛋白分子吸附自由能计算效率和精确度。基于新提出的吸附自由能计算方法，分析固液界面多肽/蛋白质分子的特异性吸附和构象变化的热力学控制机制。本项目的完成不仅为蛋白质分子在固液界面吸附自由能计算，提供新技术思路，也从能量学上定量评价新设计的生物分子结构与功能或生物材料性能，提供可能的理论途径。

本项目基于限制势能及加强构型空间取样技术，建立和发展适用于多肽/蛋白质分子在固液界面吸附自由能精确计算的分子模拟方法；通过若干具有代表性体系的研究，为选择经济且精度可靠的自由能计算方法提供了一些共性和规律性的判断标准。研究揭示界面水层与固体表面的结合强度对吸附自由能计算的准确性和效率有至关重要的影响。通过结合伞状取样技术与热力学微扰理论，成功剥离固体表面和溶剂主导的吸附自由能贡献，揭示水相诱导的自由能相是固体表面生物阻抗的热力学因素。结合多肽分子界面迁移过程中的结构分析，系统研究了不同固体-溶液-多肽界面性质（表面亲水性、多肽带电性质）对界面吸附的调节机制，增强溶剂与固体表面或溶剂与蛋白质分子的相互作用强度均能够导致表面生物阻抗行为。基于所发展的自由能理论计算方法，研究氨基酸或多肽吸附对羟基磷灰石（HAP）晶体生长的影响，从能量学上揭示了HAP（100）晶面在骨骼中作为主要表面的热力学机理。

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