The cis-trans isomerization mechanism of N-Methylacetamide was studied by molecular dynamics simulations employing a hybrid QM/MM potential with explicit water. In combination with the umbrella sampling method, we obtained the free-energy barrier between the cis-trans states in accordance with previous experimental and theoretical values. Moreover, we found that the improper dihedral angle, C(=O)-N-H-C(-H3), correlates well with the degree of the pyramidal conformations. We then investigated the role of the degree of the pyramidal conformation with respect to the isomerization processes and found that it governs the height and peak position of the free-energy barriers and the hydration structure. (C) 2011 Elsevier B. V. All rights reserved.