Abstract：
Acetyl-coenzyme A carboxylases (ACCs) is the first committed enzyme of fatty acid synthesis pathway. The inhibition of ACC is thought to be beneficial not only for diseases related to metabolism, such as type-2 diabetes, but also for infectious disease like bacterial infection disease. Soraphen A, a potent allosteric inhibitor of BC domain of yeast ACC, exhibit lower binding affinities to several yeast ACC mutants and the corresponding drug resistance mechanisms are still unknown. We report here a theoretical study of binding of soraphen A to wild type and yeast ACC mutants (including F510I, N485G, I69E, E477R, and K73R) via molecular dynamic simulation and molecular mechanics/generalized Born surface area free energy calculations methods. The calculated binding free energies of soraphen A to yeast ACC mutants are weaker than to wild type, which is highly consistent with the experimental results. The mutant F510I weakens the binding affinity of soraphen A to yeast ACC mainly by decreasing the van der Waals contributions, while the weaker binding affinities of Soraphen A to other yeast ACC mutants including N485G, I69E, E477R, and K73R are largely attributed to the decreased net electrostatic (ΔEele + ΔGGB) interactions. Our simulation results could provide important insights for the development of more potent ACC inhibitors.
摘要：
乙酰辅酶A羧化酶（ACCs）是脂肪酸合成途径的第一个关键酶。ACC的抑制被认为不仅对与代谢相关的疾病有益，比如2型糖尿病，也适用于传染病如细菌感染疾病。SoraphenA,酵母ACCBC结构域的有效变构抑制剂，对几种酵母ACC突变体表现出较低的结合亲和力，相应的耐药机制仍然未知。我们在这里报告了soraphenA与野生型和酵母ACC突变体（包括F510I，N485G,I69E,E477R,和K73R）通过分子动力学模拟和分子力学/广义Born表面积自由能计算方法。soraphenA与酵母ACC突变体的计算结合自由能比野生型弱，这与实验结果高度一致。突变体F510I主要通过降低范德华贡献来削弱soraphenA与酵母ACC的结合亲和力，虽然SoraphenA与其他酵母ACC突变体（包括N485G）的结合亲和力较弱，I69E,E477R,和K73R主要归因于净静电(ΔEele+ΔGGB)相互作用的减少。我们的模拟结果可以为开发更有效的ACC抑制剂提供重要的见解。
