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首页> 外文期刊>Journal of magnetic resonance >Theoretical Analysis of the Inter-Ligand Overhauser Effect: A New Approach for Mapping Structural Relationships of Macromolecular Ligands
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Theoretical Analysis of the Inter-Ligand Overhauser Effect: A New Approach for Mapping Structural Relationships of Macromolecular Ligands

机译：配体间过度吸收效应的理论分析：映射大分子配体结构关系的新方法

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A theoretical framework has been developed for the evaluation of inter-ligand Overhauser effects (ILOE), predicted when pairs of ligands are observed in the presence of a macromolecular receptor which can form a ternary complex such that some of the protons on the two ligands are in close proximity with each other (generally less than approx 5 A). Simulations for a pair of ligands with three spins each have been performed for a variety of geometric and rate parameters. Analogous to previously described calculations of TRNOE behavior, theoretical behavior of each of the nine cross peaks, A_(ij) in a NOESY experiment involving ligands which can exist in the free, binary, or ternary complex states can be calculated. However, for exchange which is sufficiently rapid on the relaxation and chemical shift time scales, use of a collapsed matrix, C. corresponding to sums of sets of nine elements, will often be appropriate and generally simplifies the analysis. In order to generate inter-ligand Overhauser effects, it is optimal for the fraction of receptor involved in the ternary complex to be reasonably large; i.e., concentrations of both ligands should be near saturation. Based on a model assuming random binding order of the lignads, the dependence of ILOE resonance intensities on kinetic rate constants roughly parallels the dependence of transferred NOE (TRNOE) intensities. For diffusion controlled binding, i.e., k_(on) approx 10~8 M~(-1) s~(-1), the method is best suited for equilibrium dissociation constants in the micromolar-millimolar range (k_(off) approx 10~2-10~5 s~(-1)). Toward the slower dissociation rate constant end of this range, TRNOE and ILOE effects are still predicted, but the initial build-up curves become markedly nonlinear. For a kinetic binding scheme which assumes ordered binding of the ligands, the inherent asymmetry of the ligand binding process leads to more complex kinetics and alters the dependence of the ILOE on the kinetic parameters. In this case, the binding of the second ligand effectively reduces the exchange rate of the first ligand, reducing the transfer of NOE and ILOE information. The reduction in TRNOE and ILOE information which is predicted for the ordered ligand binding model is overcome at larger dissociation rate constants for either ligand 1 or ligand 2. In addition to the structural information available from ILOE data, the strong dependence of TRNOE and ILOE curves on ordered ligand binding suggests that such measurements could be useful for the characterization of ligand binding kinetics.
机译：已经开发出用于评估配体间奥豪瑟效应（ILOE）的理论框架，该理论框架预测了在存在可以形成三元复合物的大分子受体的情况下观察到一对配体时，两个配体上的一些质子为彼此紧靠（通常小于5 A）。对于各种几何和速率参数，已经对一对具有三个自旋的配体进行了模拟。类似于先前描述的TRNOE行为的计算，在NOESY实验中，可以计算九个交叉峰A_（ij）中每个交叉峰的理论行为，该实验涉及可以以自由，二元或三元复杂状态存在的配体。但是，对于在弛豫和化学位移时间尺度上足够快速的交换，通常使用适合于九个元素的总和的折叠矩阵C.通常会简化分析。为了产生配体间Overhauser效应，最佳的是使三元复合物中所涉及的受体的比例相当大;这是优选的。即两种配体的浓度应接近饱和。基于假设枝条的随机结合顺序的模型，ILOE共振强度对动力学速率常数的依赖性大致平行​​于转移NOE（TRNOE）强度的依赖性。对于扩散控制的键合，即k_（on）约为10〜8 M〜（-1）s〜（-1），该方法最适合微摩尔-毫摩尔范围内的平衡解离常数（k_（off）约为10 〜2-10〜5 s〜（-1））。往该范围内较慢的解离速率恒定端，仍可预测TRNOE和ILOE的作用，但初始积累曲线明显变为非线性。对于假定配体有序结合的动力学结合方案，配体结合过程的固有不对称性导致更复杂的动力学，并改变了ILOE对动力学参数的依赖性。在这种情况下，第二配体的结合有效地降低了第一配体的交换速率，从而减少了NOE和ILOE信息的传递。对于较大的配体1或配体2的解离速率常数，克服了针对有序配体结合模型预测的TRNOE和ILOE信息减少的问题。除了从ILOE数据可获得的结构信息之外，TRNOE和ILOE曲线的强烈依赖性关于有序的配体结合的研究表明，这种测量对于表征配体结合动力学可能是有用的。

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