Dynamic Descriptions of Highly Flexible Molecules from NMR Dipolar Couplings: Physical Basis and Limitations

Biomolecules that control physiological function by changing their conformation play key roles in biology and remain poorly characterized. NMR dipolar couplings (DCs) depend intrinsically on both molecular shape and structural fluctuations, thereby providing the enticing prospect of tracking these conformational changes at atomic detail. Although this dual dependence has until now severely complicated analysis of DCs from highly dynamic systems, general approaches have recently been proposed that simplify interpretation of experimental DCs, by entirely eliminating molecular alignment from the analysis. Using simple and intuitive simulation of target ensembles, we investigate the impact of such approaches on the resulting descriptions of the conformational energy landscape. We find that ensemble descriptions of highly flexible systems derived from DCs without explicit consideration of the alignment properties of the constituent conformations can be compromised and inaccurate, despite exhibiting high correlation with experimental measurement.

通过改变构象调控生理功能的生物分子在生物学领域发挥着关键作用，但其相关特性至今仍未得到充分表征。核磁共振偶极耦合（NMR dipolar couplings, DCs）本质上同时依赖于分子形态与结构涨落，因而具备在原子尺度追踪构象变化的诱人前景。尽管这种双重依赖此前极大地复杂化了对高动态体系中DCs的分析，但近期已有研究提出了通用分析方法，可通过在分析过程中完全剔除分子取向因素，简化实验DCs的解读流程。我们通过对目标构象集合开展简洁直观的模拟，探究了这类方法对构象能量景观（conformational energy landscape）最终描述的影响。研究发现，尽管未明确考虑组成构象的取向特性、仅基于DCs推导得到的高柔性体系的构象集合描述与实验测量结果具有较高相关性，但这类描述可能存在缺陷且不够准确。