Zhang Jinfeng, Chen Yu, Chen Rong, Liang Jie
Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
J Chem Phys. 2004 Jul 1;121(1):592-603. doi: 10.1063/1.1756573.
Side chains of amino acid residues are the determining factor that distinguishes proteins from other unstable chain polymers. In simple models they are often represented implicitly (e.g., by spin states) or simplified as one atom. Here we study side chain effects using two-dimensional square lattice and three-dimensional tetrahedral lattice models, with explicitly constructed side chains formed by two atoms of different chirality and flexibility. We distinguish effects due to chirality and effects due to side chain flexibilities, since residues in proteins are L residues, and their side chains adopt different rotameric states. For short chains, we enumerate exhaustively all possible conformations. For long chains, we sample effectively rare events such as compact conformations and obtain complete pictures of ensemble properties of conformations of these models at all compactness region. This is made possible by using sequential Monte Carlo techniques based on chain growth method. Our results show that both chirality and reduced side chain flexibility lower the folding entropy significantly for globally compact conformations, suggesting that they are important properties of residues to ensure fast folding and stable native structure. This corresponds well with our finding that natural amino acid residues have reduced effective flexibility, as evidenced by statistical analysis of rotamer libraries and side chain rotatable bonds. We further develop a method calculating the exact side chain entropy for a given backbone structure. We show that simple rotamer counting underestimates side chain entropy significantly for both extended and near maximally compact conformations. We find that side chain entropy does not always correlate well with main chain packing. With explicit side chains, extended backbones do not have the largest side chain entropy. Among compact backbones with maximum side chain entropy, helical structures emerge as the dominating configurations. Our results suggest that side chain entropy may be an important factor contributing to the formation of alpha helices for compact conformations.
氨基酸残基的侧链是区分蛋白质与其他不稳定链状聚合物的决定性因素。在简单模型中，它们通常被隐含表示（例如，通过自旋状态）或简化为一个原子。在这里，我们使用二维正方形晶格和三维四面体晶格模型研究侧链效应，其中明确构建了由具有不同手性和柔韧性的两个原子形成的侧链。我们区分了由于手性引起的效应和由于侧链柔韧性引起的效应，因为蛋白质中的残基是L型残基，并且它们的侧链采用不同的旋转异构体状态。对于短链，我们详尽地列举了所有可能的构象。对于长链，我们有效地对诸如紧密构象等罕见事件进行采样，并获得这些模型在所有紧密区域的构象系综性质的完整图景。这是通过使用基于链增长方法的序贯蒙特卡罗技术实现的。我们的结果表明，对于全局紧密构象，手性和降低的侧链柔韧性都会显著降低折叠熵，这表明它们是残基确保快速折叠和稳定天然结构的重要性质。这与我们的发现非常吻合，即天然氨基酸残基具有降低的有效柔韧性，这通过旋转异构体文库和侧链可旋转键的统计分析得到证明。我们进一步开发了一种计算给定主链结构精确侧链熵的方法。我们表明，简单的旋转异构体计数对于伸展和接近最大紧密构象都会显著低估侧链熵。我们发现侧链熵并不总是与主链堆积密切相关。有了明确的侧链，伸展的主链并不具有最大的侧链熵。在具有最大侧链熵的紧密主链中，螺旋结构成为主导构型。我们的结果表明，侧链熵可能是促成紧密构象形成α螺旋的一个重要因素。
