Di Rienzo Lorenzo, Milanetti Edoardo, Testi Claudia, Montemiglio Linda Celeste, Baiocco Paola, Boffi Alberto, Ruocco Giancarlo
Center for Life Nanoscience, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.
Department of Physics, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Comput Struct Biotechnol J. 2020 Sep 24;18:2678-2686. doi: 10.1016/j.csbj.2020.09.020. eCollection 2020.
Protein-protein interactions regulate almost all cellular functions and rely on a fine tune of surface amino acids properties involved on both molecular partners. The disruption of a molecular association can be caused even by a single residue mutation, often leading to a pathological modification of a biochemical pathway. Therefore the evaluation of the effects of amino acid substitutions on binding, and the design of protein-protein interfaces, is one of the biggest challenges in computational biology. Here, we present a novel strategy for computational mutation and optimization of protein-protein interfaces. Modeling the interaction surface properties using the Zernike polynomials, we describe the shape and electrostatics of binding sites with an ordered set of descriptors, making possible the evaluation of complementarity between interacting surfaces. With a Monte Carlo approach, we obtain protein mutants with controlled molecular complementarities. Applying this strategy to the relevant case of the interaction between Ferritin and Transferrin Receptor, we obtain a set of Ferritin mutants with increased or decreased complementarity. The extensive molecular dynamics validation of the method results confirms its efficacy, showing that this strategy represents a very promising approach in designing correct molecular interfaces.
蛋白质-蛋白质相互作用几乎调节所有细胞功能，并且依赖于对两个分子伴侣表面氨基酸性质的精确调节。即使是单个残基突变也可能导致分子缔合的破坏，常常导致生化途径的病理改变。因此，评估氨基酸取代对结合的影响以及蛋白质-蛋白质界面的设计，是计算生物学中最大的挑战之一。在此，我们提出了一种用于蛋白质-蛋白质界面的计算突变和优化的新策略。使用泽尼克多项式对相互作用表面性质进行建模，我们用一组有序的描述符来描述结合位点的形状和静电，从而能够评估相互作用表面之间的互补性。通过蒙特卡罗方法，我们获得了具有可控分子互补性标准的蛋白质突变体。将该策略应用于铁蛋白与转铁蛋白受体相互作用的相关案例，我们获得了一组互补性增加或降低的铁蛋白突变体。该方法结果的广泛分子动力学验证证实了其有效性，表明该策略在设计正确的分子界面方面是一种非常有前景的方法。
