We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays the weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-timescale biomolecular processes from short atomistic molecular dynamics simulations. We then showcase the application of this method to the Muller Brown potential model, the conformational switching in alanine dipeptide, and the millisecond

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... le protein-ligand unbinding in the trypsin-benzamidine complex. Not only can we predict the kinetics of these processes with quantitative accuracy, but we also present a scheme to reconstruct a multidimensional free energy landscape, along additional degrees of freedom which are not part of the milestoning progress coordinate. For the ligand-receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM approach within a few hundreds of nanoseconds simulation time, which is a fraction of the computational cost of other currently available methods, and close to four orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost the M-WEM approach can find potential application in kinetics and free energy based computational drug design.