Bera Santu, Dong Xuewei, Krishnarjuna Bankala, Raab Shannon A, Hales David A, Ji Wei, Tang Yiming, Shimon Linda J W, Ramamoorthy Ayyalusamy, Clemmer David E, Wei Guanghong, Gazit Ehud
Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
Department of Physics, State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), Fudan University, Shanghai, 200433, People's Republic of China.
Cell Rep Phys Sci. 2021 Apr 21;2(4):100391. doi: 10.1016/j.xcrp.2021.100391.
The understanding and prediction of the solubility of biomolecules, even of the simplest ones, reflect an open question and unmet need. Short aromatic tripeptides are among the most highly aggregative biomolecules. However, in marked contrast, Ala-Phe-Ala (AFA) was surprisingly found to be non-aggregative and could be solubilized at millimolar concentrations. Here, aiming to uncover the underlying molecular basis of its high solubility, we explore in detail the solubility, aggregation propensity, and atomic-level structure of the tripeptide. We demonstrate an unexpectedly high water solubility of AFA reaching 672 mM, two orders of magnitude higher than reported previously. The single crystal structure reveals an anti-parallel β sheet conformation devoid of any aromatic interactions. This study provides clear mechanistic insight into the structural basis of solubility and suggests a simple and feasible tool for its estimation, bearing implications for design of peptide drugs, peptides materials, and advancement of peptide nanotechnology.
对生物分子溶解度的理解和预测，即使是最简单的生物分子，仍然是一个悬而未决的问题且存在未被满足的需求。短芳香族三肽是最易聚集的生物分子之一。然而，与之形成显著对比的是，令人惊讶地发现丙氨酸 - 苯丙氨酸 - 丙氨酸（AFA）不会聚集，并且在毫摩尔浓度下可溶解。在此，为了揭示其高溶解度背后的分子基础，我们详细探究了该三肽的溶解度、聚集倾向和原子水平结构。我们证明AFA具有出乎意料的高水溶性，达到672 mM，比之前报道的高两个数量级。单晶结构显示出一种反平行β折叠构象，不存在任何芳香族相互作用。这项研究为溶解度的结构基础提供了清晰的机制见解，并提出了一种简单可行的溶解度估算工具，对肽类药物设计、肽材料以及肽纳米技术的发展具有重要意义。
