Conformational landscape of a macrocycle from REST enhanced sampling

RESUMO

We use replica-exchange molecular dynamics (REMD) to map the conformational free-energy landscape of the macrocyclic drug lorlatinib in explicit water and chloroform. In water a single dominant basin is recovered; in chloroform two conformational states are resolved. We use these conformers as the starting point to calculate proton chemical shifts from first principles and a continuum solvent model. The resulting population-weighted spectrum is compared directly to the experimental CDCl$_3$ spectrum, benchmarking the computational approach against measured NMR data.