Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409, USA.
J Chem Phys. 2022 Jun 28;156(24):245102. doi: 10.1063/5.0096349.
Molecular photoswitches are widely used in photopharmacology, where the biomolecular functions are photo-controlled reversibly with high spatiotemporal precision. Despite the success of this field, it remains elusive how the protein environment modulates the photochemical properties of photoswitches. Understanding this fundamental question is critical for designing more effective light-regulated drugs with mitigated side effects. In our recent work, we employed first-principles non-adiabatic dynamics simulations to probe the effects of protein on the trans to cis photoisomerization of phototrexate (PTX), a photochromic analog of the anticancer therapeutic methotrexate that inhibits the target enzyme dihydrofolate reductase (DHFR). Building upon this study, in this work, we employ multiscale simulations to unravel the full photocycle underlying the light-regulated reversible inhibition of DHFR by PTX, which remains elusive until now. First-principles non-adiabatic dynamics simulations reveal that the cis to trans photoisomerization quantum yield is hindered in the protein due to backward isomerization on the ground-state following non-adiabatic transition, which arises from the favorable binding of the cis isomer with the protein. However, free energy simulations indicate that cis to trans photoisomerization significantly decreases the binding affinity of the PTX. Thus, the cis to trans photoisomerization most likely precedes the ligand unbinding from the protein. We propose the most probable photocycle of the PTX-DHFR system. Our comprehensive simulations highlight the trade-offs among the binding affinity, photoisomerization quantum yield, and the thermal stability of the ligand's different isomeric forms. As such, our work reveals new design principles of light-regulated drugs in photopharmacology.
分子光开关广泛应用于光药理学中，其中生物分子功能可通过高时空精度的光控制进行可逆调控。尽管该领域取得了成功，但蛋白质环境如何调节光开关的光化学性质仍然难以捉摸。理解这个基本问题对于设计更有效的光调节药物，减轻副作用至关重要。在我们最近的工作中，我们采用第一性原理非绝热动力学模拟来研究蛋白质对光致变色类似物 phototrexate（PTX）的顺式到反式光异构化的影响，PTX 是抗癌治疗药物 methotrexate 的光致变色类似物，可抑制靶酶二氢叶酸还原酶（DHFR）。基于这项研究，在这项工作中，我们采用多尺度模拟来揭示光调节可逆抑制 DHFR 所涉及的完整光循环，这在以前是难以捉摸的。第一性原理非绝热动力学模拟表明，由于非绝热跃迁后基态的反向异构化，顺式到反式光异构化量子产率在蛋白质中受到阻碍，这是由于 cis 异构体与蛋白质的有利结合所致。然而，自由能模拟表明 cis 到 trans 光异构化显著降低了 PTX 的结合亲和力。因此，cis 到 trans 光异构化很可能先于配体从蛋白质中释放。我们提出了 PTX-DHFR 系统最可能的光循环。我们的综合模拟强调了配体不同异构体形式的结合亲和力、光异构化量子产率和热稳定性之间的权衡。因此，我们的工作揭示了光药理学中光调节药物的新设计原则。
