Pharmaceutical Development, Genentech, South San Francisco, California.
Pharmaceutical Development, Genentech, South San Francisco, California.
Biophys J. 2020 Jun 2;118(11):2741-2754. doi: 10.1016/j.bpj.2020.04.022. Epub 2020 Apr 29.
Self-association of therapeutic monoclonal antibodies (mabs) are thought to modulate the undesirably high viscosity observed in their concentrated solutions. Computational prediction of such a self-association behavior is advantageous early during mab drug candidate selection when material availability is limited. Here, we present a coarse-grained (CG) simulation method that enables microsecond molecular dynamics simulations of full-length antibodies at high concentrations. The proposed approach differs from others in two ways: first, charges are assigned to CG beads in an effort to reproduce molecular multipole moments and charge asymmetry of full-length antibodies instead of only localized charges. This leads to great improvements in the agreement between CG and all-atom electrostatic fields. Second, the distinctive hydrophobic character of each antibody is incorporated through empirical adjustments to the short-range van der Waals terms dictated by cosolvent all-atom molecular dynamics simulations of antibody variable regions. CG simulations performed on a set of 15 different mabs reveal that diffusion coefficients in crowded environments are markedly impacted by intermolecular interactions. Diffusion coefficients computed from the simulations are in correlation with experimentally measured observables, including viscosities at a high concentration. Further, we show that the evaluation of electrostatic and hydrophobic characters of the mabs is useful in predicting the nonuniform effect of salt on the viscosity of mab solutions. This CG modeling approach is particularly applicable as a material-free screening tool for selecting antibody candidates with desirable viscosity properties.
治疗性单克隆抗体（mab）的自缔合被认为可以调节其浓缩溶液中观察到的不理想的高粘度。在候选 mab 药物选择的早期阶段，当材料可用性有限时，对这种自缔合行为进行计算预测是有利的。在这里，我们提出了一种粗粒度（CG）模拟方法，该方法能够在高浓度下对全长抗体进行微秒分子动力学模拟。所提出的方法与其他方法有两个不同之处：首先，在 CG 珠粒上分配电荷，以努力再现全长抗体的分子多极矩和电荷不对称性，而不仅仅是局部电荷。这导致 CG 和全原子静电场之间的一致性有了很大的提高。其次，通过对抗体可变区的溶剂化全原子分子动力学模拟来调整短程范德华项，从而将每个抗体的独特疏水性特征纳入其中。对 15 种不同 mab 的一组 CG 模拟表明，在拥挤环境中的扩散系数明显受到分子间相互作用的影响。从模拟中计算出的扩散系数与实验测量的可观察值相关，包括高浓度下的粘度。此外，我们还表明，评估 mab 的静电和疏水性质对于预测盐对 mab 溶液粘度的非均匀影响是有用的。这种 CG 建模方法特别适用于作为一种无材料的筛选工具，用于选择具有理想粘度特性的抗体候选物。
