Wallqvist A, Jernigan R L, Covell D G
Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, Maryland 21702, USA.
Protein Sci. 1995 Sep;4(9):1881-903. doi: 10.1002/pro.5560040923.
The interface between protein receptor-ligand complexes has been studied with respect to their binary interatomic interactions. Crystal structure data have been used to catalogue surfaces buried by atoms from each member of a bound complex and determine a statistical preference for pairs of amino-acid atoms. A simple free energy model of the receptor-ligand system is constructed from these atom-atom preferences and used to assess the energetic importance of interfacial interactions. The free energy approximation of binding strength in this model has a reliability of about +/- 1.5 kcal/mol, despite limited knowledge of the unbound states. The main utility of such a scheme lies in the identification of important stabilizing atomic interactions across the receptor-ligand interface. Thus, apart from an overall hydrophobic attraction (Young L, Jernigan RL, Covell DG, 1994, Protein Sci 3:717-729), a rich variety of specific interactions is observed. An analysis of 10 HIV-1 protease inhibitor complexes is presented that reveals a common binding motif comprised of energetically important contacts with a rather limited set of atoms. Design improvements to existing HIV-1 protease inhibitors are explored based on a detailed analysis of this binding motif.
蛋白质受体 - 配体复合物的界面已就其二元原子间相互作用进行了研究。晶体结构数据已被用于编目结合复合物中每个成员的原子所掩埋的表面，并确定氨基酸原子对的统计偏好。受体 - 配体系统的一个简单自由能模型由这些原子 - 原子偏好构建而成，并用于评估界面相互作用的能量重要性。尽管对未结合状态的了解有限，但该模型中结合强度的自由能近似具有约±1.5千卡/摩尔的可靠性。这种方案的主要用途在于识别受体 - 配体界面上重要的稳定原子相互作用。因此，除了整体疏水吸引力（Young L，Jernigan RL，Covell DG，1994，Protein Sci 3：717 - 729）之外，还观察到了丰富多样的特异性相互作用。本文给出了对10种HIV - 1蛋白酶抑制剂复合物的分析，揭示了一个由与相当有限的一组原子的能量重要接触组成的共同结合基序。基于对该结合基序的详细分析，探索了对现有HIV - 1蛋白酶抑制剂的设计改进。
