Thirumoorthy Krishnan, Nandi Nilashis
Chemistry Department, Kalyani University, Kalyani, 741 235, West Bengal, India.
J Phys Chem B. 2008 Jul 31;112(30):9187-95. doi: 10.1021/jp8032066. Epub 2008 Jul 9.
We present a theoretical analysis of the role of the natural chirality of the sugar ring ( D-enantiomeric form) in the peptide synthesis reaction in ribosome. The study is based on a model from the crystal structure of the ribosomal subunit of Haloarcula marismortui using hybrid quantum mechanical-molecular mechanical method. The result indicates that the natural heterochiral sugar-amino acid combination ( D: L) is most favorable for the formation of the peptide bond within the structure of peptidyl transferase center (PTC). Other possible combinations of unnatural chiral form of the sugar-amino acid pair are unfavorable to perform the reaction within the PTC. The presence of the sugar ring has favorable influence on the rotatory path. The chirality of the 2' carbon of the sugar ring is vital for the peptide synthesis. Alteration of the stereochemistry or removal of chirality at the 2' center makes the rate as several orders slower in magnitude. This is in agreement with the recent experimental result that the replacement of the 2' OH by H or F reduces the rate by several orders of magnitude. Two different mechanisms for the catalytic effect of the stereochemistry of 2' OH are investigated. In one mechanism, the 2' OH is involved in proton shuttle, and in the second mechanism, the OH group acts as an anchoring group. The transition state barriers of both mechanisms are found to be comparable. The natural chirality of the 2' center helps lowering the transition state barrier height of the reaction substantially compared with the cases where the 2' center is made achiral or with altered chirality. Thus, the stereochemistry of the 2' center has a major role in synthesis. Few surrounding residues like U2620, A2486, G2618, and C2487 have favorable influence on rotatory path, while the residues like U2541, C2104, C2105, A2485, C2542, C2608, U2619, and A2637 have little influence. The present study shows that the natural chirality of the sugar ring and amino acid makes a perfect heteropair within the PTC to carry out peptide synthesis with high efficiency.
我们对核糖体中肽合成反应中糖环（D - 对映体形式）的天然手性作用进行了理论分析。该研究基于使用量子力学 - 分子力学混合方法对嗜盐栖热菌核糖体亚基晶体结构建立的模型。结果表明，天然的异手性糖 - 氨基酸组合（D：L）最有利于在肽基转移酶中心（PTC）结构内形成肽键。糖 - 氨基酸对的其他非天然手性形式的可能组合不利于在PTC内进行反应。糖环的存在对旋转路径有有利影响。糖环2'碳的手性对肽合成至关重要。2'中心立体化学的改变或手性的去除使反应速率在数量级上慢几个数量级。这与最近的实验结果一致，即2'位的OH被H或F取代会使反应速率降低几个数量级。研究了2' OH立体化学催化作用的两种不同机制。在一种机制中，2' OH参与质子穿梭，在第二种机制中，OH基团充当锚定基团。发现两种机制的过渡态能垒相当。与2'中心变为非手性或手性改变的情况相比，2'中心的天然手性有助于大幅降低反应的过渡态能垒高度。因此，2'中心的立体化学在合成中起主要作用。少数周围残基如U2620、A2486、G2618和C2487对旋转路径有有利影响，而残基如U2541、C2104、C2105、A2485、C2542、C2608、U2619和A2637影响很小。本研究表明，糖环和氨基酸的天然手性在PTC内形成了完美的异对，以高效进行肽合成。
