ENTHALPY ENTROPY COMPENSATIONS IN DRUG DNA-BINDING STUDIES
ENTHALPY ENTROPY COMPENSATIONS IN DRUG DNA-BINDING STUDIES
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DOI：
10.1073/pnas.84.24.8922
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发表时间：
1987-12-01
影响因子：
11.1
通讯作者：
MARKY, LA
中科院分区：
文献类型：
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作者：
BRESLAUER, KJ;REMETA, DP;MARKY, LA
我们提出了一系列药物与选定的DNA宿主双链体结合的量热热力学曲线的比较研究。我们使用这些数据来证明，在药物结合可以用作DNA构象的探针之前，需要比较完整的热力学分布(差值G度，差值H度，差值度，差值Cp)，因为热熵补偿可以使两个药物-DNA结合事件显示出相似的结合自由能(差值。)尽管是由完全不同的热力学作用力(差值、差值)驱动的。在这项工作中，我们使用光谱和量热技术相结合的方法来表征Netropsin和地塞米松(两个次要的沟槽定向配体)、乙锭(嵌入剂)和柔红霉素(嵌入剂/沟槽结合剂)与DNA的结合。我们的自由能数据(ΔG)表明，每种药物在25度时都表现出类似的结合亲和力。C为交替共聚物双链聚[d(A-T)].cntdo.Poly[d(A-T)]和均聚物双链Poly(Da).保利(DT)。然而，我们的量热测量表明，热力学力的性质(ΔH度，ΔS度)这促使药物以25度与这两个宿主双链结合。C是完全不同的，尽管结合自由能相似(？)和类似的盐依赖关系(.vdelta.InK/.vdelta.In[Na+])。具体地说，二十五度。C所有四种药物与交替共聚物聚[d(A-T)].cntdot的结合。Poly[d(A-T)]绝大多数是由焓驱动的，而每种药物对应的结合到均聚物双链Poly(Da).cntdo.保利(DT)是压倒性的熵驱动。因此，相似的结合自由能(ΔG度)我们测量每种药物与聚[d(A-T)].cntdot的络合作用。Poly[d(A-T)]和Poly(Da).cntdo.Poly(DT)是通过补偿热焓和熵项的变化而产生的。比较了这些药物分子与其他DNA宿主双链体在25度时的络合热力学曲线。C揭示了每个分子的结合都是强焓驱动的，除了当聚(Da).cntpoint时。聚(DT)均聚物作为主体双链。通过这种比较，我们可以得出这样的结论：聚[d(A-T)].cntdot。Poly[d(A-T)]的热力学行为更像是药物结合的“正常”主机双链，而熵驱动的结合则是Poly(Da).cntdot。Poly(DT)双工表示“异常”行为。此外，由于四种药物中的每一种都表现出不同的DNA结合模式，我们得出结论，所观察到的与聚(Da).cntdot结合的熵驱动行为。Poly(DT)反映了均聚双链的固有性质，该性质在连接时以共同的方式被扰动，而不是所有四个结合配体的共同性质。使驱动药物与聚(Da).cntdot络合的大的正熵变化合理化。Poly(DT)双链，我们提出了一个模型，强调结合诱导的扰动更高水合，改变的B构象的均聚物。我们的结果表明，异常的热力学结合谱可能反映了宿主双链中不寻常的DNA构象。然而，在得出这样的结论之前，必须检查完整的热力学结合谱，因为焓-熵补偿可以导致两个结合事件表现出相似的结合常数，即使它们是由非常不同的热力学作用力驱动的。
We present a comparative study of calorimetrically derived thermodynamic profiles for the binding of a series of drugs with selected DNA host duplexes. We use these data to demonstrate that comparisons between complete thermodynamic profiles (.DELTA.G.degree., .DELTA.H.degree., .DELTA.S.degree., .DELTA.Cp) are required before drug binding can be used as a probe of DNA conformation, since enthalpy-entropy compensations can cause two drug-DNA binding events to exhibit similar binding free energies (.DELTA.G.degree.) despite being driven by entirely different thermodynamic forces (.DELTA.H.degree., .DELTA.S.degree.). In this work, we employ a combination of spectroscopic and calorimetric techniques to characterize thermodynamically the DNA binding of netropsin and distamycin (two minor groove-directed ligands), ethidium (an intercalator), and daunomycin (a combined intercalator/groove binder). Our free energy data (.DELTA.G)) show that each drug exhibits similar binding affinities at 25.degree. C for the alternating copolymer duplex poly[d(A-T)] .cntdot. poly[d(A-T)] and for the homopolymer duplex poly(dA) .cntdot. poly(dT). However, our calorimetric measurements reveal that the nature of the thermodynamic forces (.DELTA.H.degree., .DELTA.S.degree.) that drive drug binding to these two host duplexes at 25.degree. C are entirely different, despite similar binding free energies (.DELTA.G.degree.) and similar salt dependencies (.vdelta.InK/.vdelta.In[Na+]). Specifically, the 25.degree. C binding of all four drugs to the alternating copolymer poly[d(A-T)] .cntdot. poly[d(A-T)] is overwhelmingly enthalpy driven, whereas the corresponding binding of each drug to the homopolymer duplex poly(dA) .cntdot. poly(dT) is overwhelmingly entropy driven. Thus, the similar binding free energies (.DELTA.G.degree.) we measure for complexation of each drug with poly[d(A-T)] .cntdot. poly[d(A-T)] and poly(dA) .cntdot. poly(dT) result from compensating changes in the enthalpy and entropy terms. Comparison with the thermodynamic profiles for the complexation of these drug molecules to other DNA host duplexes at 25.degree. C reveals that the binding of each is strongly enthalpy driven, except when the poly(dA) .cntdot. poly(dT) homopolymer serves as the host duplex. This comparison allows us to conclude that poly[d(A-T)] .cntdot. poly[d(A-T)] behaves thermodynamically as the more "normal" host duplex toward drug binding, whereas the entropy-driven binding to the poly(dA) .cntdot. poly(dT) duplex represents "aberrant" behavior. Furthermore, since each of the four drugs exhibits different modes of DNA binding, we conclude that the observed entropy-driven behavior for binding to poly(dA) .cntdot. poly(dT) reflects an intrinsic property of the homopolymer duplex that is perturbed in a common manner upon ligation rather than a common property of all four binding ligands. To rationalize the large positive entropy changes that drive drug complexation with the poly(dA) .cntdot. poly(dT) duplex, we propose a model that emphasizes binding-induced perturbations of the more highly hydrated, altered B conformation of the homopolymer. Our results suggest that an aberrant thermodynamic binding profile may reflect an unusual DNA conformation in the host duplex. However, before such a conclusion can be reached, complete thermodynamic binding profiles must be examined, since enthalpy-entropy compensations can cause two binding events to exhibit similar binding constants even when they are driven by very different thermodynamic forces.