Collagen stability: Insights from NMR spectroscopic and hybrid density functional computational investigations of the effect of electronegative substituents on prolyl ring conformations
Collagen stability: Insights from NMR spectroscopic and hybrid density functional computational investigations of the effect of electronegative substituents on prolyl ring conformations
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DOI：
10.1021/ja0166904
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发表时间：
2002-03-20
影响因子：
15
通讯作者：
Markley, JL
中科院分区：
文献类型：
--
作者：
DeRider, ML;Wilkens, SJ;Markley, JL
胶原蛋白样肽类型（Pro-Pro-Gly）（10）折叠成稳定的三螺旋。在第二脯氨酸残基的H-γ 3环位置处的吸电子取代基稳定这些三重螺旋。本研究的目的是揭示这种效应的结构和能量来源。该方法是获得模型系统的实验NMR数据，并使用这些结果来验证这些系统的计算化学分析。吸电子取代基最显著的影响是对取代的脯氨酸（Pro）的环褶皱和Xaa（j-1）-Pro（j）肽键的反式/顺式比率的影响。NMR实验表明，N-乙酰基脯氨酸甲酯（AcProOMe）以C-γ-内和C-γ-外构象两者存在（内构象稍微优选），N-乙酰基-4（R）-氟脯氨酸甲酯（Ac-4 R-FIpOMe）几乎仅以C-γ-外构象存在，并且N-乙酰基-4（S）-氟脯氨酸乙酯（Ac-4SFIpOMe）几乎仅以C-γ-内构象存在。在二氧六环中，AcProOMe、Ac-4 R-FIpOMe和Ac-4S-FlpOMe的K-反式/顺式值分别为3.0、4.0和1.2。密度泛函理论（DFT）计算（混合）B3 LYP方法与实验数据符合良好。自然键轨道（NBO）范式的计算分析表明，取代脯氨酰环的褶皱偏好是由于gauche效应。主链扭转角phi和psi显示与环起皱相关，环起皱又与胶原蛋白样肽中已知的phi和psi角相关。AcProOMe和Ac-4 R-FIpOMe之间的K-反式/顺式的差异是由于与Burgi-Dunitz轨迹相关的n -> pi（*）相互作用。Ac-4S-FIpOMe的Ktranss/cis的降低可以通过反式异构体的不稳定来解释，这是由于不利的电子和空间相互作用。对本文的结果连同胶原蛋白样肽的结构的分析沿着产生了将胶原蛋白稳定性与吡咯烷环褶皱、phi和psi扭转角以及取代的脯氨酸残基的肽键反式/顺式比率之间的相互作用联系起来的理论。
Collagen-like peptides of the type (Pro-Pro-Gly)(10) fold into stable triple helices. An electron-withdrawing substituent at the H-gamma3 ring position of the second proline residue stabilizes these triple helices. The aim of this study was to reveal the structural and energetic origins of this effect. The approach was to obtain experimental NMR data on model systems and to use these results to validate computational chemical analyses of these systems. The most striking effects of an electron-withdrawing substituent are on the ring pucker of the substituted proline (Pro) and on the trans/cis ratio of the Xaa(j-1)-Pro(j) peptide bond. NMR experiments demonstrated that N-acetylproline methyl ester (AcProOMe) exists in both the C-gamma-endo and C-gamma-exo conformations (with the endo conformation slightly preferred), N-acetyl-4(R)-fluoroproline methyl ester (Ac-4R-FIpOMe) exists almost exclusively in the C-gamma-exo conformation, and N-acetyl-4(S)-fluoroproline ethyl ester (Ac-4SFIpOMe) exists almost exclusively in the C-gamma-endo conformation. In dioxane, the K-trans/cis values for AcProOMe, Ac-4R-FIpOMe, and Ac-4S-FlpOMe are 3.0, 4.0, and 1.2, respectively. Density functional theory (DFT) calculations with the (hybrid) B3LYP method were in good agreement with the experimental data. Computational analysis with the natural bond orbital (NBO) paradigm shows that the pucker preference of the substituted prolyl ring is due to the gauche effect. The backbone torsional angles, phi and psi, were shown to correlate with ring pucker, which in turn correlates with the known phi and psi angles in collagen-like peptides. The difference in K-trans/cis between AcProOMe and Ac-4R-FIpOMe is due to an n --> pi(*) interaction associated with the Burgi-Dunitz trajectory. The decrease in Ktrans/cis for Ac-4S-FIpOMe can be explained by destabilization of the trans isomer because of unfavorable electronic and steric interactions, Analysis of the results herein along with the structures of collagen-like peptides has led to a theory that links Collagen stability to the interplay between the pyrrolidine ring pucker, phi and psi torsional angles, and peptide bond trans/cis ratio of substituted proline residues.