Accurate Description of Cation−π Interactions in Proteins with a Nonpolarizable Force Field at No Additional Cost

Abstract

Cation−π interactions play a significant role in a host of processes eminently relevant to biology. However, polarization effects arising from the interaction of cations with aromatic moieties have long been recognized to be inadequately described by pairwise additive force fields. In the present work, we address this longstanding shortcoming through the nonbonded FIX (NBFIX) feature of the CHARMM36 force field, modifying pair-specific Lennard–Jones (LJ) parameters, while circumventing the limitations of the Lorentz–Berthelot combination rules. The potentials of mean force (PMFs) characterizing prototypical cation−π interactions in aqueous solutions are first determined using a hybrid quantum mechanical/molecular mechanics (QM/MM) strategy in conjunction with an importance-sampling algorithm. The LJ parameters describing the cation−π pairs are then optimized to match the QM/MM PMFs. The standard binding free energies of nine cation−π complexes, i.e., toluene, para-cresol, and 3-methyl-indole interacting with either ammonium, guanidinium, or tetramethylammonium, determined with this new set of parameters agree well with the experimental measurements. Additional simulations were carried out on three different classes of biological objects featuring cation−π interactions, including five individual proteins, three protein–ligand complexes, and two protein–protein complexes. Our results indicate that the description of cation−π interactions is overall improved using NBFIX corrections, compared with the standard pairwise additive force field. Moreover, an accurate binding free energy calculation for a protein–ligand complex containing cation−π interactions (2BOK) shows that using the new parameters, the experimental binding affinity can be reproduced quantitatively. Put together, the present work suggests that the NBFIX parameters optimized here can be broadly utilized in the simulation of proteins in an aqueous solution to enhance the representation of cation−π interactions, at no additional computational cost.

Standard binding free energy and membrane desorption mechanism for a phospholipase C

“…We are confident that the CHARMM-WYF parameters for the treatment of interactions between choline headgroups and aromatic residues (F, Y and W) 47,48 are unlikely to contribute to an overestimation of those interactions given the earlier validation of these parameters against experimental 13,68 and quantum mechanics data. 47,48 On the other hand, the contribution of the inserted tryptophans W47 and W242 could be overestimated.…”

Accurate Estimation of Protein-ligand Binding Free Energies Based on Geometric Restraints

“…本课题组采用基于七自由度约束和重要性采样策 略, 研究了纺锤菌素和 DNA 的结合能力(图 5), 将准确 结合自由能计算方法拓展到了任意主体-客体体系 [59] ; 探究了碗烯和苝在结合蛋白质能力上的差异, 阐明了具 有立体结构的碗烯在和蛋白质作用上的优势 [60] . 由于 诸多研究证明了蛋白质-配体准确结合自由能计算策略 的可靠性, 本课题组将蛋白质-配体标准结合自由能作 为一个考察参数引入力场拟合步骤当中, 并通过计算蛋 白质-配体结合自由能, 验证拟合的力场参数的可靠 性 [61] .…”

Benchmarking London dispersion corrected density functional theory for noncovalent ion-pi interactions

“…61 The development of such FFs and respective workflows is an emerging field of research, especially with respect to the efficient description of ion-π interactions in proteins. 62,63 First, a brief survey of the employed semi-classical LDcorrection schemes is given followed by a description of the compiled IONPI19 benchmark set. Further, the results for this test set are presented and discussed for all employed methods.…”