Molecular Simulation of Stapled Peptides.

Constrained peptides represent a relatively new class of biologic therapeutics, which have the potential to overcome several limitations of small-molecule drugs, and of designed antibodies. Because of their modest size, the rational design of such peptides is becoming increasingly amenable to computer simulation; multi-microsecond molecular dynamic (MD) simulations are now routinely possible on consumer-grade graphical processors (GPUs). Here, we describe the procedures for performing and analyzing MD simulations of hydrocarbon-stapled peptides using the CHARMM energy function, in isolation and in complex with a binding partner, to investigate their conformational properties and to compute changes in their binding affinity upon mutation.