Macrocycle Conformational Sampling with MacroModel

• Published in: Journal of chemical information and modeling 2014-10, Vol.54 (10), p.2680-2696
• Main Authors: Watts, K. Shawn, Dalal, Pranav, Tebben, Andrew J, Cheney, Daniel L, Shelley, John C
• Format: Article
• Language: English
• Subjects: Algorithms; Cyclodextrins - chemistry; Median; Molecular Conformation; Molecular Dynamics Simulation; Molecules; Peptides - chemistry; Peptides, Cyclic - chemistry; Proteins - chemistry; Sampling; Simulation; Software; Thermodynamics; Values
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci5001696

Sampling low energy conformations of macrocycles is challenging due to the large size of many of these molecules and the constraints imposed by the macrocycle. We present a new conformational search method (implemented in MacroModel) that uses brief MD simulations followed by minimization and normal-mode search steps. The method was parametrized using a set of 100 macrocycles from the PDB and CSD. It was then tested on a publicly available data set for which there are published results using alternative methods; we found that when the same force field is used (in this case MMFFs in vacuum), our method tended to identify conformations with lower energies than what the other methods identified. The performance on a new set of 50 macrocycles from the PDB and CSD was also quite good; the mean and median RMSD values for just the ring atoms were 0.60 and 0.33 Å, respectively. However, the RMSD values for macrocycles with more than 30 ring-atoms were quite a bit larger compared to the smaller macrocycles. Possible origins for this and ideas for improving the performance on very large macrocycles are discussed.