The human cytochrome P450 1A2 is an important drug metabolizing and procarcinogen activating enzyme. An experimental study found that a peripheral mutation, F186L, at ∼26 Å away from the enzyme's active site, caused a significant reduction in the enzymatic activity of 1A2 deethylation reactions. In this paper, we explored the effects of this mutation by carrying out molecular dynamics simulations and structural analyses. We found that the long-range effects of the F186L mutation were through a change in protein flexibility and a collective protein motion that caused the main substrate access channel to be mostly closed in the mutant. Our work is the first that combined both access channel analysis and protein motion analysis to elucidate mechanisms of mutation-induced allostery in a CYP protein. Such structural modeling and analysis approaches may be applied to other CYP proteins and other enzymes with buried active sites and may help guide protein engineering and drug design.