Peptide Binding to β-Cyclodextrins: Structure, Dynamics, Energetics, and Electronic Effects

Abstract

Peptide-cyclodextrin and protein-cyclodextrin host-guest complexes are becoming more and more important for industrial applications, in particular in the fields of pharmaceutical and food chemistry. They have already deserved many experimental investigations although the effect of complex formation in terms of peptide (or protein) structure is not well-known yet. Theoretical calculations represent a unique tool to analyze such effects, and with this aim we have carried out in the present investigation molecular dynamics simulations and combined quantum mechanics-molecular mechanics calculations. We have studied complexes formed between the model Ace-Phe-Nme peptide and the β-cyclodextrin (β-CD) macromolecule, and our analysis focuses on the following points: (1) how is the peptide structure modified in going from bulk water to CD environment (backbone torsion angles), (2) which are the main peptide-CD interactions, in particular in terms of hydrogen bonds, (3) which relative peptide-CD orientation is preferred and which are the structural and energetic differences between them, and (4) how the electronic properties of the peptide changes under complex formation. Overall, our calculations show that in the most stable configuration, the backbone chain lies in the narrow rim of the CD. Strong hydrogen bonds form between the H atoms of the peptidic NH groups and oxygen atoms of the secondary OH groups in the CD. These and other (weaker) hydrogen bonds formed by the carbonyl groups reduce considerably the flexibility of the peptide structure, compared to bulk water, and produce a marked increase of the local dipole moment by favoring configurations in which the two C═O bonds point toward the same direction. This effect might have important consequences in terms of the peptide secondary structure, although this hypothesis needs to be tested using larger peptide models.

Topological Aspects of the Design of Nanocarriers for Therapeutic Peptides and Proteins

“…Cyclodextrins (CDs) are cyclic oligosaccharides built of glucopyranose [16]. The most common CD species consist of six (α-CD), seven (β-CD), or eight (γ-CD) sugar units.…”

Cyclodextrin Modulated Type I Collagen Self‐Assembly to Engineer Biomimetic Cornea Implants

“…To determine potential specific interactions between the CDs and collagen molecules, we evaluated the UV absorbance of collagen solutions with αCD, βCD, γCD, and βCD‐Suc (Figure c and Figure S3, Supporting Information). βCD is known to bind with polypeptides containing aromatic groups such as tyrosine, as measured by a shift in wavelength or increase in absorbance at the characteristic tyrosine peak at 275 nm. Collagen was combined with the CDs at pH 3 in 1 × 10 −3 m HCl solution to avoid gelation, and the potential interactions of CD with collagen could be isolated.…”

Investigation on Non-Covalent Complexes of Cyclodextrins with GGG and GFF Tripeptides in Gas Phase by Mass Spectrometry

“…此后不久, Lebrilla 等 [22] 用客体交换反应质谱实 验并结合理论计算, 提出了不同的观点, 即有证据证明 环糊精和苯丙氨酸、酪氨酸、亮氨酸等在液相和气相中 均可以形成特异性结合的包合物, 只是它们在结构上略 有差异. 最近, Yeguas 等 [23] 采用分子动力学模拟结合量 子力学-分子力学理论计算了含有苯基的 Ace-Phe-Nme 多肽与 β-环糊精的反应, 计算结果表明多肽的骨架链位 于环糊精的小口, 并且 NH 基团上的氢原子和环糊精仲 羟基上的氧原子形成了较强的氢键, 量子力学模拟的复 合物的优势构象显示, 苯基位于环糊精的小口内.…”

“…由于环糊精和三肽反应后, 得到配合比为 1∶1 的 复合物, 所以可以采用文献 [3] [23] 曾经指出特异性结合指的是客体包合在环 糊精的疏水腔体内, 而非特异性结合指的是客体包合在 环糊精的疏水腔体外. 当环糊精和客体分子在溶液中形 成主客体包合物时, 其主要驱动力为主体和客体非极性 部分的去溶剂化, 即疏水作用.…”