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.

中文翻译：

---

深入了解酵母乙酰辅酶A羧化酶突变体F510I，N485G，I69E，E477R和K73R对soraphen A产生抗性的分子机制。

乙酰辅酶A羧化酶（ACC）是脂肪酸合成途径中第一个固定的酶。认为ACC的抑制不仅有益于与代谢有关的疾病，例如2型糖尿病，而且还有益于传染性疾病，例如细菌感染性疾病。Soraphen A（一种有效的酵母ACC BC域的变构抑制剂）对几个酵母ACC突变体的结合亲和力较低，并且相应的耐药机制仍然未知。我们在这里报告通过分子动力学模拟和分子力学/广义生表面积自由能计算方法将索拉芬A与野生型和酵母ACC突变体（包括F510I，N485G，I69E，E477R和K73R）结合的理论研究。计算得出的soraphen A对酵母ACC突变体的结合自由能比对野生型弱，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减弱soraphen A与酵母ACC的结合亲和力，而Soraphen A与包括N485G，I69E，E477R和K73R在内的其他酵母ACC突变体的结合亲和力较弱的主要原因是净静电（ΔEele+ΔGGB）相互作用。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识。和K73R很大程度上归因于净静电（ΔEele+ΔGGB）相互作用的降低。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识。和K73R很大程度上归因于净静电（ΔEele+ΔGGB）相互作用的降低。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识。