Delle Piane Massimo, Corno Marta, Orlando Roberto, Dovesi Roberto, Ugliengo Piero
Department of Chemistry and NIS Centre , University of Torino , via Pietro Giuria 7 , 10125 , Torino , Italy . Email:
Chem Sci. 2016 Feb 1;7(2):1496-1507. doi: 10.1039/c5sc03447g. Epub 2015 Nov 24.
Molecular simulations of proteins have been usually accomplished through empirical or semi-empirical potentials, due to the large size and inherent complexity of these biological systems. On the other hand, a theoretical description of proteins based on quantum-mechanical methods would however provide an unbiased characterization of their electronic properties, possibly offering a link between these and the ultimate biological activity. Yet, such approaches have been historically hindered by the large amount of requested computational power. Here we demonstrate the feasibility of periodic all-electron density functional theory calculations in the description of the crystal of the protein crambin (46 aminoacids), which is determined with exceptional structural accuracy. We have employed the hybrid B3LYP functional, coupled to an empirical description of London interactions (D*) to simulate the crambin crystal with an increasing amount of lattice water molecules in the cell (up to 172HO per cell). The agreement with the experiment is good for both protein geometry and protein-water interactions. The energetics was computed to predict crystal formation energies, protein-water and protein-protein interaction energies. We studied the role of dispersion interactions which are crucial for holding the crambin crystal in place. B3LYP-D* electrostatic potential and dipole moment of crambin as well as the electronic charge flow from crambin to the solvating water molecules (0.0015 per HO) have also been predicted. These results proved that quantum-mechanical simulations of small proteins, both free and in their crystalline state, are now feasible in a reasonable amount of time, by programs capable of exploiting high performance computing architectures, allowing the study of protein properties not easily amenable through classical force fields.
由于蛋白质这类生物系统规模庞大且内在复杂，其分子模拟通常是通过经验或半经验势来完成的。另一方面，基于量子力学方法对蛋白质进行理论描述，将能提供对其电子性质的无偏表征，有可能在这些性质与最终生物活性之间建立联系。然而，此类方法一直以来因所需计算能力巨大而受到阻碍。在此，我们证明了周期性全电子密度泛函理论计算在描述胰凝乳蛋白酶原（46个氨基酸）晶体方面的可行性，该晶体结构测定具有极高的精度。我们采用了杂化B3LYP泛函，并结合伦敦相互作用的经验描述（D*），来模拟细胞中晶格水分子数量不断增加（每个细胞最多172个H₂O）的胰凝乳蛋白酶原晶体。在蛋白质几何结构和蛋白质 - 水相互作用方面，与实验结果的吻合度都很高。通过计算能量来预测晶体形成能、蛋白质 - 水和蛋白质 - 蛋白质相互作用能。我们研究了色散相互作用在维持胰凝乳蛋白酶原晶体结构稳定方面的关键作用。还预测了B3LYP - D*的静电势、胰凝乳蛋白酶原的偶极矩以及从胰凝乳蛋白酶原到溶剂化水分子的电子电荷流动（每个H₂O为0.0015）。这些结果证明，借助能够利用高性能计算架构的程序，对游离态和晶体态的小蛋白质进行量子力学模拟在合理时间内已成为可能，这使得通过经典力场难以研究的蛋白质性质得以开展研究。
