Seven-membered ring mimetics of mannose were studied as ligands for the mannose-specific bacterial lectin FimH, which plays an essential role in the first step of urinary tract infections (UTI). A competitive binding assay and isothermal titration calorimetry (ITC) experiments indicated an approximately ten-fold lower affinity for the seven-membered ring mannose mimetic 2-O-n-heptyl-1,6-anhydro-D-glycero-D-galactitol (7) compared to n-heptyl α-D-mannopyranoside (2), resulting exclusively from a loss of conformational entropy. Investigations by solution NMR, X-ray crystallography, and molecular modeling revealed that 7 establishes a superimposable H-bond network compared to mannoside 2, but at the price of a high entropic penalty due to the loss of its pronounced conformational flexibility. These results underscore the importance of having access to the complete thermodynamic profile of a molecular interaction to “rescue” ligands from entropic penalties with an otherwise perfect fit to the protein binding site.

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灵活性的代价–以琼脂糖为吡喃糖模拟物的案例研究

研究了甘露糖的七元环模拟物作为甘露糖特异性细菌凝集素FimH的配体，后者在泌尿道感染（UTI）的第一步中起着至关重要的作用。竞争性结合测定和等温滴定量热法（ITC）的实验表明为七元环甘露糖模拟物2-约10倍的亲和力低论-庚基-1,6-脱水- d -甘油基- d -galactitol（7）与正庚基α- D-甘露吡喃糖苷（2）相比，完全是由于构象熵的损失。通过溶液NMR，X射线晶体学和分子建模的研究表明7建立了与甘露糖苷2相比可重叠的H键网络，但是由于丧失了其明显的构象灵活性，因此付出了高熵代价。这些结果强调了获得分子相互作用的完整热力学图谱以从熵损失中“挽救”配体并以其他方式完美适合蛋白质结合位点的重要性。