Multicanonical molecular dynamics simulations combined with Metadynamics for the free energy landscape of a biomolecular system with high energy barriers

► Combined McMD with MetaD method was applied to the free energy calculations of a proline dipeptide. ► MetaD was performed and a coarse biasing potential was obtained. ► Using the biasing potential, McMD realized an enhanced sampling for all degrees-of-freedom. ► An accurate free energy landscape is obtained after reweighting.