Exploring XXXX egress channels in human cytochrome P450 2A6 by random acceleration and steered molecular dynamics simulations.

@entity1524 @entity815 @entity5944
The kinetic analysis of @entity1524 oxidation by @entity5944 suggested that substrate binding and release occurred in the multiple steps and such events proceeded rapidly. However, the crystal structure of the @entity5944 - @entity1524 complex reveals that no obvious channel is open enough to allow @entity1524 to pass through. Thus, an intriguing and important question arises: how @entity1524 enters and exits the active site, which is deeply buried at the center of @entity5944 fold. In this study, geometric analysis of the potential openings was first performed on all the available crystal structures of @entity5944 . And then, random acceleration molecular dynamics simulations were used to explore the possible substrate egress channels in @entity5944 . Two channels were most frequently observed. Afterwards, steered molecular dynamics simulations were performed and potentials of mean force were constructed to compare the preference of the two channels serving as the substrate egress channel. The results showed that channel 2c, which is located between helices I and G and the helix B'-C region, was the most likely channel for @entity1524 egress. The opening of channel 2c was characterized by a rotation of @entity815 111 together with a bending of helix B'. Our findings will not only be helpful for understanding the unbinding mechanism of @entity1524 and for identifying structural determinants related to the biological function of @entity5944 , but also provide further insight into the channel selectivity of P450s.
