Molecular dynamics (MD) simulations are often described as a being an ultra-high resolution microscope that can observe the dynamic behaviour of molecules. While this is true to a large extent, MD simulations suffer from some well-known limitations, particularly that it is difficult to observe rare events using MD. For example, while it is straightforward to model the dynamics of a receptor-ligand complex it is difficult to use MD to observe the actual ligand binding event.
In our current work, we have utilised an enhanced-sampling MD method, parallel cascade molecular dynamics1 (PaCS-MD), to accelerate the association of peptide ligands with their protein binding sites, enabling the complex process of peptide binding to be observed in detail. Although PaCS-MD has previously been used to model disassociation of protein-peptide complexes, to our knowledge, it has not been used in the forward direction. We have used PaCS-MD to model the binding trajectories of a range of peptides to their target proteins, including G protein coupled receptors, revealing the key processes of peptide ligand binding. Further, we have combined PaCS-MD trajectories with Markov-state models to calculate free energies of binding. The PaCS-MD method also provides useful information for molecular design. We will discuss our studies on angiotensin II, neurotensin 8-13 and inhibitors of the SPSB2-iNOS interaction.