H
2
O
2
, is an attractive oxidant for synthetic chemistry, especially if activated as percarboxylic acid. H
2
O
2
, however, is also a potent inactivator of enzymes. Protein engineering efforts to improve enzyme resistance against H
2
O
2
in the past have mostly focused on tedious probabilistic directed evolution approaches. Here we demonstrate that a rational approach combining multiscale MD simulations and Born-Oppenheimer ab initio QM/MM MD simulations is an efficient approach to rapidly identify improved enzyme variants. Thus, the lipase from Penicillium camembertii was redesigned with a single mutation (I260R), leading to drastic improvements in H
2
O
2
resistance while maintaining the catalytic activity. Also the extension of this methodology to other enzymes is demonstrated.
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