Bogetti Anthony T, Piston Hannah E, Leung Jeremy M G, Cabalteja Chino C, Yang Darian T, DeGrave Alex J, Debiec Karl T, Cerutti David S, Case David A, Horne W Seth, Chong Lillian T
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Molecular Biophysics and Structural Biology Graduate Program, University of Pittsburgh and Carnegie Mellon University, Pittsburgh, Pennsylvania 15260, USA.
J Chem Phys. 2020 Aug 14;153(6):064101. doi: 10.1063/5.0019054.
We present a new force field, AMBER ff15ipq-m, for simulations of protein mimetics in applications from therapeutics to biomaterials. This force field is an expansion of the AMBER ff15ipq force field that was developed for canonical proteins and enables the modeling of four classes of artificial backbone units that are commonly used alongside natural α residues in blended or "heterogeneous" backbones: chirality-reversed D-α-residues, the C-methylated α-residue Aib, homologated β-residues (β) bearing proteinogenic side chains, and two cyclic β residues (β; APC and ACPC). The ff15ipq-m force field includes 472 unique atomic charges and 148 unique torsion terms. Consistent with the AMBER IPolQ lineage of force fields, the charges were derived using the Implicitly Polarized Charge (IPolQ) scheme in the presence of explicit solvent. To our knowledge, no general force field reported to date models the combination of artificial building blocks examined here. In addition, we have derived Karplus coefficients for the calculation of backbone amide J-coupling constants for βAla and ACPC β residues. The AMBER ff15ipq-m force field reproduces experimentally observed J-coupling constants in simple tetrapeptides and maintains the expected conformational propensities in reported structures of proteins/peptides containing the artificial building blocks of interest-all on the μs timescale. These encouraging results demonstrate the power and robustness of the IPolQ lineage of force fields in modeling the structure and dynamics of natural proteins as well as mimetics with protein-inspired artificial backbones in atomic detail.
我们提出了一种新的力场AMBER ff15ipq-m，用于模拟从治疗到生物材料等应用中的蛋白质模拟物。该力场是为规范蛋白质开发的AMBER ff15ipq力场的扩展，能够对四类人工主链单元进行建模，这些单元通常与天然α残基一起用于混合或“异质”主链中：手性反转的D-α-残基、C-甲基化α-残基Aib、带有蛋白原侧链的同系化β-残基（β），以及两个环状β残基（β；APC和ACPC）。ff15ipq-m力场包括472个独特的原子电荷和148个独特的扭转项。与AMBER IPolQ系列力场一致，电荷是在存在明确溶剂的情况下使用隐式极化电荷（IPolQ）方案推导出来的。据我们所知，迄今为止报道的没有一般力场能对这里研究的人工构建块的组合进行建模。此外，我们还推导了用于计算β-丙氨酸和ACPC β残基主链酰胺J-耦合常数的Karplus系数。AMBER ff15ipq-m力场在简单的四肽中再现了实验观察到的J-耦合常数，并在包含感兴趣的人工构建块的蛋白质/肽的报道结构中保持了预期的构象倾向——所有这些都是在微秒时间尺度上。这些令人鼓舞的结果证明了IPolQ系列力场在以原子细节模拟天然蛋白质以及具有蛋白质启发的人工主链的模拟物的结构和动力学方面的能力和稳健性。
