Sippl M J, Ortner M, Jaritz M, Lackner P, Flöckner H
Center for Applied-Molecular Engineering, University of Salzburg, Austria.
Fold Des. 1996;1(4):289-98. doi: 10.1016/S1359-0278(96)00042-9.
Proteins fold to unique three-dimensional structures, but how they achieve this transition and how they maintain their native folds is controversial. Information on the functional form of molecular interactions is required to address these issues. The basic building blocks are the free energies of atom pair interactions in dense protein solvent systems. In a dense medium, entropic effects often dominate over internal energies but free energy estimates are notoriously difficult to obtain. A prominent example is the peptide hydrogen bond (H-bond). It is still unclear to what extent H-bonds contribute to protein folding and stability of native structures.
Radial distribution functions of atom pair interactions are compiled from a database of known protein folds. The functions are transformed to Helmholtz free energies using a recipe from the statistical mechanics of dense interacting systems. In particular we concentrate on the features of the free energy functions of peptide H-bonds. Differences in Helmholtz free energies correspond to the reversible work required or gained when the distance between two particles is changed. Consequently, the functions directly display the energetic features of the respective thermodynamic process, such as H-bond formation or disruption.
In the H-bond potential, a high barrier isolates a deep narrow minimum at H-bond contact from large distances, but the free energy difference between H-bond contact and large distances is close to zero. The energy barrier plays an intriguing role in H-bond formation and disruption: both processes require activation energy in the order of 2kT. H-bond formation opposes folding to compact states, but once formed, H-bonds act as molecular locks and a network of such bonds keeps polypeptide chains in a precise spatial configuration. On the other hand, peptide H-bonds do not contribute to the thermodynamic stability of native folds, because the energy balance of H-bond formation is close to zero.
蛋白质折叠成独特的三维结构，但其如何实现这种转变以及如何维持其天然折叠状态仍存在争议。需要有关分子相互作用功能形式的信息来解决这些问题。基本组成部分是致密蛋白质溶剂系统中原子对相互作用的自由能。在致密介质中，熵效应通常比内能占主导地位，但自由能估计 notoriously 难以获得。一个突出的例子是肽氢键（H键）。目前仍不清楚H键在多大程度上有助于蛋白质折叠和天然结构的稳定性。
从已知蛋白质折叠的数据库中汇编原子对相互作用的径向分布函数。使用来自致密相互作用系统统计力学的方法将这些函数转换为亥姆霍兹自由能。特别是，我们专注于肽H键自由能函数的特征。亥姆霍兹自由能的差异对应于当两个粒子之间的距离改变时所需或获得的可逆功。因此，这些函数直接显示了各自热力学过程的能量特征，例如H键的形成或破坏。
在H键势中，一个高势垒将H键接触处的深窄极小值与大距离隔离开来，但H键接触与大距离之间的自由能差接近零。能量势垒在H键的形成和破坏中起着有趣的作用：这两个过程都需要约2kT量级的活化能。H键的形成不利于折叠成紧凑状态，但一旦形成，H键就像分子锁，这样的键网络使多肽链保持在精确的空间构型中。另一方面，肽H键对天然折叠的热力学稳定性没有贡献，因为H键形成的能量平衡接近零。
