Before revision:  In this paper, we make a first step towards MSM/RD by laying out a general theory of coupling and proposing a first implementation that includes both conformational changes and association/dissociation of proteins with small ligands or substrates . Applications on a toy model and CO diffusion and binding to myoglobin are reported.
After revision:  In this paper, we make a first step towards MSM/RD by laying out a general theory of coupling and proposing a first implementation that includes both conformational changes and association/dissociation of proteins with small ligands or substrates . Applications on a toy model and CO diffusion into the heme cavity of myoglobin are reported.