A CONTINUUM MODEL FOR PROTEIN-PROTEIN INTERACTIONS - APPLICATION TO THE DOCKING PROBLEM
A CONTINUUM MODEL FOR PROTEIN-PROTEIN INTERACTIONS - APPLICATION TO THE DOCKING PROBLEM
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DOI：
10.1006/jmbi.1995.0375
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发表时间：
1995-07-07
影响因子：
5.6
通讯作者：
STERNBERG, MJE
中科院分区：
文献类型：
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作者：
JACKSON, RM;STERNBERG, MJE
预测蛋白质-蛋白质在溶液中的相互作用是理论结构生物学的一个主要目标，我们实现了对所涉及的热力学过程的连续描述。该模型与以往的模型有很大的不同，它用分子表面面积来描述疏水组分在溶液中的构象变化自由能。我们已经将这个模型应用于蛋白质-蛋白质复合体的替代对接构象的数据集，这些构象是独立于这项工作产生的。以前发现，常用的能量评估技术不能区分该数据集中的近自然复合体和某些非自然复合体。在这里，我们发现一个考虑(1)总静电自由能，(2)疏水自由能和(3)侧链构象能损失的能量函数能够可靠地区分近天然和非天然构型，但只有当分子表面被用作疏水效应的描述符时。结果表明，分子表面和更传统的表面描述符“溶剂可及表面”给出了非常不同的疏水性定量度量。根据不同能量组分对络合物自由能的贡献，发现侧链构象熵的损失是一种二级效应。当从非结合构象开始时，静电相互作用能(通常用来计算对接构象)是一个很差的互补性指标。研究发现，与点对点相互作用能相比，静电脱溶能和疏水贡献(基于分子表面积描述符)对原子结构的局部波动不那么敏感，因此可能更适合作为对接非结合构象时的评分函数，其中原子互补性要明显得多。虽然组合能量函数能够在这里研究的六个系统中区分近自然构象和非自然构象，但更大的构象变化将在多大程度上影响结果仍有待确定。
The prediction of protein-protein interactions in solution is a major goal of theoretical structural biology Here, we implement a continuum description of the thermodynamic processes involved. The model differs considerably from previous models in its use of ''molecular surface'' area to describe the hydrophobic component to the free energy of conformational change in solution. We have applied this model to a data set of alternative docked conformations of protein-protein complexes which were generated independently of this work. It was found previously that commonly used energy evaluation techniques fail to distinguish between near-native and certain non-native complexes in this data set. Here, we found that an energy function that takes into account (1) total electrostatic free energy, (2) hydrophobic free energy and (3) loss in side-chain conformational energy was able to reliably discriminate between near-native and non-native configurations but only when molecular surface is used as a descriptor of the hydrophobic effect. It is shown that the molecular surface and the more conventional surface descriptor ''solvent accessible surface'' give very different quantitative measures of hydrophobicity. In terms of the contribution of different energy components to the free energy of complex formation it was found that loss in side-chain conformational entropy is a second order effect. Electrostatic interaction energy (which is commonly used to score docked conformations) was a poor indicator of complementarity when starting from unbound conformations. It was found that electrostatic desolvation energy and the hydrophobic contribution (based on a molecular surface area descriptor) are much less sensitive to local fluctuations in atomic structure than point-to-point interaction energies and thus may be more suited for use as a scoring function when docking unbound conformations, where atomic complementarity is much less apparent. Whilst a combined energy function was able to distinguish near-native from non-native conformations in the six systems studied here, it remains to be determined to what extent more sizeable conformational changes would influence the results.