We provide insight into the first stages of a kinetic mechanism of lateral drug expulsion from the active site of HIV-1 protease, by conducting all atom molecular dynamics simulations with explicit solvent over a time scale of 24 ns for saquinavir bound to the wildtype, G48V, L90M and G48V/L90M mutant proteases. We find a consistent escape mechanism associated with the G48V mutation. First, increased hydrophilic and hydrophobic flap coupling and water mediated disruption of catalytic dyad hydrogen bonding induce drug motion away from the dyad and promote protease flap transition to the semi-open form. Conversely, flap-inhibitor motion is decoupled in the wildtype. Second, the decrease of total interactions causes unidirectional lateral inhibitor translation by up to 4 A toward the P3 subsite exit of the active site, increased P3 subsite exposure to solvent and a complete loss of hydrophobic interactions with the opposite end of the active site. The P1 subsite moves beyond the hydrophobic active site side pocket, the only remaining steric barrier to complete expulsion being the "breathable" residue, P81. Significant inhibitor deviation is reported over 24 ns, and subsequent complete expulsion, implemented using steered molecular dynamics simulations, is shown to occur most easily for the G48V-containing mutants. Our simulations thus provide compelling support for lateral drug escape from a protease in a semi-open flap conformation. It is likely that some mutations take advantage of this escape mechanism to increase the rate of inhibitor dissociation from the protease. Finally, unidirectional translation may be countered by designing inhibitors with terminal subsites that provide sufficient anchoring to the flaps, thus increasing the steric barrier for translation in either direction.