Macrocycle Conformational Sampling by DFT-D3/COSMO-RS Methodology

To find and calibrate a robust and reliable computational protocol for mapping conformational space of medium-sized molecules, exhaustive conformational sampling has been carried out for a series of seven macrocyclic compounds of varying ring size and one acyclic analogue. While five of them were taken from the MD/LLMOD/force field study by Shelley and co-workers ( Watts , K. S. ; Dalal , P. ; Tebben , A. J. ; Cheney , D. L. ; Shelley , J. C. Macrocycle Conformational Sampling with MacroModel . J. Chem. Inf. MODEL: ) than the latter (i.e., plain SQM MD). The CPU time needed to fully evaluate one medium-sized compound (∼100 atoms, typically resulting in several hundred or a few thousand conformers generated and treated quantum-mechanically) is approximately 1,000-100,000 CPU hours on today's computers, which transforms to 1-7 days on a small-sized computer cluster with a few hundred CPUs. Finally, our data sets based on the rigorous quantum-chemical approach allow us to formulate a composite conformational sampling protocol with multiple checkpoints and truncation of redundant structural data that offers superior insights at affordable computational cost.