DataSheet1_Decoding the secrets: how conformational and structural regulators inhibit the human 20S proteasome.PDF

Acquired resistance to drugs that modulate specific protein functions, such as the human proteasome, presents a significant challenge in targeted therapies. This underscores the importance of devising new methodologies to predict drug binding and potential resistance due to specific protein mutations. In this work, we conducted an extensive computational analysis to ascertain the effects of selected mutations (Ala49Thr, Ala50Val, and Cys52Phe) within the active site of the human proteasome. Specifically, we sought to understand how these mutations might disrupt protein function either by altering protein stability or by impeding interactions with a clinical administered drug. Leveraging molecular dynamics simulations and molecular docking calculations, we assessed the effect of these mutations on protein stability and ligand affinity. Notably, our results indicate that the Cys52Phe mutation critically impacts protein-ligand binding, providing valuable insights into potential proteasome inhibitor resistance.

针对调控特定蛋白质功能的药物，如人类蛋白酶体（human proteasome），其引发的获得性耐药是靶向治疗领域面临的重大挑战。这凸显了开发新方法以预测药物结合以及特定蛋白质突变引发的潜在耐药性的重要性。本研究针对人类蛋白酶体活性位点内的选定突变（Ala49Thr、Ala50Val及Cys52Phe）开展了大规模计算分析，以明确其影响。具体而言，本研究旨在阐明这些突变如何通过改变蛋白质稳定性或阻碍与临床给药药物的相互作用，破坏蛋白质功能。本研究借助分子动力学模拟（molecular dynamics simulations）与分子对接计算（molecular docking calculations），评估了这些突变对蛋白质稳定性及配体亲和力的影响。值得注意的是，本研究结果显示Cys52Phe突变会对蛋白质-配体结合产生显著影响，为理解蛋白酶体抑制剂潜在耐药性提供了宝贵见解。