Department of Biotechnology , National Institute of Pharmaceutical Education and Research , Ahmedabad , Gujarat 380054 , India.
Department of Chemistry , University of Konstanz , Konstanz 78464 , Germany.
J Chem Theory Comput. 2019 Feb 12;15(2):1453-1462. doi: 10.1021/acs.jctc.8b01138. Epub 2019 Jan 30.
Biocompatible nanostructures play an important role in drug delivery and tissue engineering applications. Controlled growth of peptide-based nanoparticles with specific morphology needs an understanding of the role of the sequence and solvation properties. In a previous combined experimental-computational study, we identified factors that govern the formation of well-defined aggregates by self-assembled pentapeptides using single amino acid substitution ( Mishra , N. K. ; Jain , A. ; Peter , C. ; Verma , S. J. Phys. Chem. B 2017 , 121 , 8155 - 8161 ). The atomistic simulation study suggested a subtle interplay between various peptide properties like rigidity/flexibility, hydrogen bonding, partitioning of aromatic residues, and dimerization of peptides that determine the different morphologies, while the overall aggregation propensity was mostly determined by the composition of the methanol/water solvent mixture. The size of the simulated aggregates and the time scales were rather restricted due to the atomistic character of the study. Here, we present an extension to a coarse-grained representation that allows for much larger system sizes and longer time scales. To this end, we have optimized a MARTINI model so that it can deal with a system that relies on local structure formation. We combine information on local behavior from atomistic studies and apply supportive dihedral angles together with local adjustment of the bead types to find the right interplay of solvent and peptides. Finally, to mimic the dimers, an introduction of additional bonds between the monomers was necessary. By adding the modifications stepwise, we were able to disentangle the influences of the various contributions, like the rigidity/flexibility of the peptides, dimer formation, or nonbonded properties of the beads, on the overall aggregation propensity and morphology of the nanoparticles. The obtained models resemble the experimental and atomistic behavior and are able to provide mechanistic insight into peptide nanoparticle formation.
生物相容性纳米结构在药物输送和组织工程应用中起着重要作用。通过控制基于肽的纳米颗粒的特定形态的生长，需要了解序列和溶剂化性质的作用。在之前的联合实验-计算研究中，我们确定了通过使用单一氨基酸取代自组装五肽形成明确定义的聚集体的因素（ Mishra, N. K. ; Jain, A. ; Peter, C. ; Verma, S. J. Phys. Chem. B 2017, 121, 8155 - 8161 ）。原子模拟研究表明，各种肽性质（刚性/柔性、氢键、芳族残基的分配以及肽的二聚化）之间存在微妙的相互作用，这些性质决定了不同的形态，而总体聚集倾向主要由甲醇/水溶剂混合物的组成决定。由于研究的原子性质，模拟聚集体的大小和时间尺度受到限制。在这里，我们提出了一个粗粒度表示的扩展，它允许更大的系统大小和更长的时间尺度。为此，我们已经优化了一个 MARTINI 模型，以便它可以处理依赖于局部结构形成的系统。我们结合了来自原子研究的局部行为信息，并应用支持的二面角并结合局部调整珠型来找到溶剂和肽之间的正确相互作用。最后，为了模拟二聚体，有必要在单体之间引入额外的键。通过逐步添加修改，我们能够分解各种贡献的影响，例如肽的刚性/柔性、二聚体形成或珠型的非键性质，对纳米颗粒的整体聚集倾向和形态的影响。所获得的模型类似于实验和原子模拟行为，并且能够提供肽纳米颗粒形成的机制见解。
