Curtin Health Innovation Research Institute, Western Australian Biomedical Research Institute, School of Biomedical Sciences and School of Pharmacy, Curtin University, GPO Box U1987, Perth WA 6845, Australia.
J Chem Inf Model. 2010 Dec 27;50(12):2201-12. doi: 10.1021/ci100321h. Epub 2010 Nov 23.
The leucine zipper region of activator protein-1 (AP-1) comprises the c-Jun and c-Fos proteins and constitutes a well-known coiled coil protein-protein interaction motif. We have used molecular dynamics (MD) simulations in conjunction with the molecular mechanics/Poisson-Boltzmann generalized-Born surface area [MM/PB(GB)SA] methods to predict the free energy of interaction of these proteins. In particular, the influence of the choice of solvation model, protein force field, and water potential on the stability and dynamic properties of the c-Fos-c-Jun complex were investigated. Use of the AMBER polarizable force field ff02 in combination with the polarizable POL3 water potential was found to result in increased stability of the c-Fos-c-Jun complex. MM/PB(GB)SA calculations revealed that MD simulations using the POL3 water potential give the lowest predicted free energies of interaction compared to other nonpolarizable water potentials. In addition, the calculated absolute free energy of binding was predicted to be closest to the experimental value using the MM/GBSA method with independent MD simulation trajectories using the POL3 water potential and the polarizable ff02 force field, while all other binding affinities were overestimated.
激活蛋白-1（AP-1）的亮氨酸拉链区域由 c-Jun 和 c-Fos 蛋白组成，构成了一个众所周知的卷曲螺旋蛋白-蛋白相互作用基序。我们使用分子动力学（MD）模拟结合分子力学/泊松-玻尔兹曼广义 Born 表面积（MM/PB（GB）SA）方法来预测这些蛋白质的相互作用自由能。特别是，研究了溶剂化模型、蛋白质力场和水势对 c-Fos-c-Jun 复合物稳定性和动力学性质的影响。使用 AMBER 极化力场 ff02 与极化 POL3 水势相结合，发现 c-Fos-c-Jun 复合物的稳定性增加。MM/PB（GB）SA 计算表明，与其他非极化水势相比，使用 POL3 水势的 MD 模拟得到的相互作用自由能预测值最低。此外，使用 POL3 水势和极化 ff02 力场的独立 MD 模拟轨迹的 MM/GBSA 方法预测的绝对结合自由能最接近实验值，而所有其他结合亲和力都被高估了。
