配体-受体结合动力学的解读
On the interpretation of the kinetics of ligand-receptor binding
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- University College London（伦敦大学学院）
- University of Cambridge（剑桥大学）
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中文总结 AI 辅助
本文针对配体结合引发受体构象变化的三状态模型，分析三种特殊情况，指出多数情况下测量速率可估算接近宏观平衡常数的配体结合平衡常数，仅结合远快于构象变化时存在例外。
中文摘要 AI 辅助
当通过表面等离子体共振等方法测量配体结合速率时，通常会利用观测到的结合起始与解离的速率常数来估算配体结合的平衡常数。若该估算值与通过平衡态结合得到的EC50（半数有效浓度）所确定的平衡常数一致，则认为测量的速率得到验证。这一结论仅在结合未引发受体构象变化、且配体结合遵循单指数时间进程时成立。本文研究了一个简单的三状态模型，其中配体结合后会引发受体构象变化，分析了该模型下配体结合起始与解离时间进程接近单指数的三种特殊情况：（1）结合速率远快于构象变化速率；（2）构象变化速率远快于结合速率；（3）配体解离与受体激活速率均较快。研究得出结论：测量的速率通常能给出接近有效（宏观）平衡常数的配体结合平衡常数估算值，该有效平衡常数由平衡态结合测量得到的EC50决定，且取决于描述配体结合与构象变化的两个基础微观平衡常数。唯一例外情况是结合速率远快于后续构象变化的情况，不过此时配体结合平衡常数的估算值仍取决于两个基础微观平衡常数。
英文摘要
When the rates of ligand binding are measured by methods such as surface plasmon resonance, it is common practice to use the observed rate constants for the onset and offset of binding to estimate an equilibrium constant for ligand binding. If this agrees with the equilibrium constant found as the EC50 for binding at equilibrium, this is taken as validation of the measured rates. This is correct only when binding produces no conformation change in the receptor, and ligand binding follows a single exponential time course. Here, we investigate a simple 3 state model in which binding is followed by a conformation change in the receptor. Three special cases of this model in which the time course of onset and offset of ligand binding are close to being single exponentials are analysed. These cases are (1) when binding is much faster than the conformation change, (2) when the conformation change is much faster than binding, and (3) when the rates of ligand dissociation and receptor activation are both fast. It is concluded that the measured rates will often yield an estimate of the equilibrium constant for ligand binding that is close to the effective, or macroscopic, equilibrium constant, the EC50 found by measuring binding at equilibrium, which depends on both of the underlying microscopic equilibrium constants describing ligand binding and the conformation change. The exception to this conclusion is the case when binding is much faster than the subsequent conformation change, though the estimate of the equilibrium constant for ligand binding still depends on both of the underlying microscopic equilibrium constants.
