Where Z w is the position of the wall along Z; k w = 5 kcal/mol/Å 4 is the wall's spring constant, H(Z) is a smooth approximation of the Heaviside step function; and k H = 10 Å -2 sets the steepness of the approximation. By default, we use a wide wall at Z=250 Å 2 . The wall is mostly inactive so as to capture the full conformational complexity of the binding pocket while avoiding the previously mentioned numerical instabilities. It is possible to use tighter walls to guarantee sampling inside a tighter egress channel along the egress path and limit computation from off-path kinetic traps, however, we did not find a systematic way to set this width a priori and leave the wall width as a parameter for system-specific fine-tuning.