Le Nguyen Ngoc Lan, Tichacek Ondrej, Jungwirth Pavel, Martinez-Seara Hector, Mason Philip E, Duboué-Dijon Elise
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 542, 160 00 Praha 6, Czech Republic.
Université Paris Cité, CNRS, Laboratoire de Biochimie Théorique, 13 rue Pierre et Marie Curie, 75005, Paris, France.
Phys Chem Chem Phys. 2025 Jan 29;27(5):2553-2562. doi: 10.1039/d4cp04312j.
Tetramethylammonium (TMA) is a ubiquitous cationic motif in biochemistry, found in the charged choline headgroup of membrane phospholipids and in tri-methylated lysine residues, which modulates histone-DNA interactions and impacts epigenetic mechanisms. TMA interactions with anionic species, particularly carboxylate groups of amino acid residues and extracellular sugars, are of substantial biological relevance, as these interactions mediate a wide range of cellular processes. This study investigates the molecular interactions between TMA and acetate, representing carboxylate-containing groups, using neutron scattering experiments complemented by force fields and molecular dynamics (MD) simulations. Neutron diffraction with isotopic substitution reveals specific ion pairing signatures between TMA and acetate, with simulations providing a detailed interpretation of the ion pairing structures. Force fields, notably CHARMM36 with the electronic continuum correction (ECC) (by a factor of 0.85) and AMBER99SB, capture essential pairing characteristics, but only revPBE-based MD simulations accurately model specific experimental features such as the low peak intensity in reciprocal space. Our study delivers a refined molecular model of TMA-carboxylate interactions, guiding the selection of force fields for complex biological systems where such interactions are of significant importance.
四甲基铵（TMA）是生物化学中普遍存在的阳离子基序，存在于膜磷脂带电荷的胆碱头部基团以及三甲基化的赖氨酸残基中，它可调节组蛋白与DNA的相互作用并影响表观遗传机制。TMA与阴离子物种的相互作用，特别是氨基酸残基的羧基和细胞外糖类的相互作用，具有重要的生物学意义，因为这些相互作用介导了广泛的细胞过程。本研究利用中子散射实验，并辅以力场和分子动力学（MD）模拟，研究了TMA与代表含羧基基团的乙酸根之间的分子相互作用。同位素取代的中子衍射揭示了TMA与乙酸根之间特定的离子配对特征，模拟为离子配对结构提供了详细解释。力场，特别是带有电子连续介质校正（ECC）（系数为0.85）的CHARMM36和AMBER99SB，捕捉了基本的配对特征，但只有基于revPBE的MD模拟能够准确模拟特定的实验特征，如倒易空间中的低峰强度。我们的研究提供了一个完善的TMA-羧基相互作用分子模型，为在这类相互作用至关重要的复杂生物系统中选择力场提供了指导。
