Ringhofer S, Kallen J, Dutzler R, Billich A, Visser A J, Scholz D, Steinhauser O, Schreiber H, Auer M, Kungl A J
Institut für Theoretische Chemie, Universität Wien, Währingerstr. 17, Wien, A-1090, Austria.
J Mol Biol. 1999 Mar 5;286(4):1147-59. doi: 10.1006/jmbi.1998.2533.
Based on the X-ray structure of the human immunodeficiency virus type-1 (HIV-1) protease in complex with the statine-derived inhibitor SDZ283-910, a 542 ps molecular dynamics trajectory was computed. For comparison with the 805 ps trajectory obtained for the uncomplexed enzyme, the theoretical fluorescence anisotropy decay of the unliganded protease and the inhibitor complex was calculated from the trajectories of the Trp6A/Trp6B and Trp42A/Trp42B transition dipole moments. This enabled us to directly compare the simulated data with the experimental picosecond time-resolved fluorescence data. Fitting both experimental and simulated data to the Kohlrausch-Williams-Watts (KWW) function exp(-t/tauk)beta revealed a very good agreement for the uncomplexed protease as well as for the SDZ283-910 complex. Binding of the inhibitor induced a faster decay of both the experimental and the computed protease fluorescence anisotropy decay. By this integrative approach, the atomic detail of inhibitor-induced changes in the conformational dynamics of the HIV-1 protease was experimentally verified and will be used for further inhibitor optimisation.
基于人类免疫缺陷病毒1型（HIV-1）蛋白酶与他汀衍生抑制剂SDZ283-910复合物的X射线结构，计算了一条542皮秒的分子动力学轨迹。为了与未复合酶的805皮秒轨迹进行比较，从未结合蛋白酶和抑制剂复合物的轨迹中计算了色氨酸6A/色氨酸6B和色氨酸42A/色氨酸42B跃迁偶极矩的理论荧光各向异性衰减。这使我们能够直接将模拟数据与实验皮秒时间分辨荧光数据进行比较。将实验数据和模拟数据都拟合到科尔劳施-威廉姆斯-瓦特（KWW）函数exp(-t/tauk)β，结果表明未复合蛋白酶以及SDZ283-910复合物的数据拟合得非常好。抑制剂的结合导致实验和计算得到的蛋白酶荧光各向异性衰减都更快。通过这种综合方法，实验验证了抑制剂诱导HIV-1蛋白酶构象动力学变化的原子细节，并将用于进一步优化抑制剂。
