Macrocycle Conformational Sampling with MacroModel

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.