Stability of macromolecular complexes
Stability of macromolecular complexes
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DOI：
10.1002/prot.10139
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发表时间：
2002-09-01
影响因子：
2.9
通讯作者：
Kuntz, ID
中科院分区：
文献类型：
--
作者：
Brooijmans, N;Sharp, KA;Kuntz, ID
大分子相互作用在许多生物过程中都是至关重要的，然而很少有一般的原则可以建立对这些相互作用强度的坚定期望或特定力的预期贡献。最简单的原理是，随着界面大小的增加，交互作用会单调地增加。确切的关系可能是线性的或非线性的，这取决于所涉及的力的性质。基于原子性质的简单的“线性自由能量”关系已经被很好地记录了，例如，小分子与溶剂相互作用的可加性，并且最近已经探索了配体与受体的相互作用。Horton和Lewis基于蛋白质-蛋白质复合物的埋藏表面积提出了这种可加性。我们研究了大分子相互作用，发现最高亲和力的复合物不满足这个简单的期望。相反，最紧密的大分子复合物的结合自由能大致是恒定的，与界面大小无关，但DNA双链体除外。通过将这些结果与早期蛋白质-配体相互作用的研究结果进行比较，我们发现：(1)最大亲和力约为每个非氢原子1.5千卡/摩尔或埋表面积120千卡/摩尔埃(2)，与我们早期工作的结果相当；(2)亲和度不随界面尺寸增加可能是由于非热力学因素，如功能和进化约束，而不是一些基本的物理限制。这些结果对分子设计具有重要意义，因为它们表明：(1)如果需要，任何给定复合物的稳定性都可以显著提高；(2)大分子相互作用的小分子抑制剂是可行的；(3)不同功能类别的蛋白质-蛋白质复合物在最大稳定性方面表现出差异，这可能是对不同进化压力的反应。这些结果与广泛的观察一致，即蛋白质没有进化到最大化热力学稳定性，而只是略微稳定。蛋白质2002;48:645 - 653。(C) 2002 Wiley-Liss, Inc。
Macromolecular interactions are crucial in numerous biologic processes, yet few general principles are available that establish firm expectations for the strength of these interactions or the expected contribution of specific forces. The simplest principle would be a monotonic increase in interactions as the size of the interface grows. The exact relationship might be linear or nonlinear depending on the nature of the forces involved. Simple "linear-free energy" relationships based on atomic properties have been well documented , for example, additivity for the interaction of small molecules with solvent, and, recently, have been explored for ligand-receptor interactions. Horton and Lewis propose such additivity based on buried surface area for protein-protein complexes. We investigated macromolecular interactions and found that the highest-affinity complexes do not fulfill this simple expectation. Instead, binding free energies of the tightest macromolecular complexes are roughly constant, independent of interface size, with the notable exception of DNA duplexes. By comparing these results to an earlier study of protein-ligand interactions we find that: (1) The maximum affinity is approximately 1.5 kcal/mol per nonhydrogen atom or 120 cal/mol Angstrom(2) of buried surface area, comparable to results of our earlier work; (2) the lack of an increase in affinity with interface size is likely due to nonthermodynamic factors, such as functional and evolutionary constraints rather than some fundamental physical limitation. The implication of these results have some importance for molecular design because they suggest that: (1) The stability of any given complex can be increased significantly if desired; (2) small molecule inhibitors of macromolecular interactions are feasible; and (3) different functional classes of protein-protein complexes exhibit differences in maximal stability, perhaps in response to differing evolutionary pressures. These results are consistent with the widespread observation that proteins have not evolved to maximize thermodynamic stability, but are only marginally stable. Proteins 2002;48:645-653. (C) 2002 Wiley-Liss, Inc.