Large-scale conformational rearrangement of a lid subdomain is a key event in the interfacial activation of many lipases. We present herein a study in which the large-scale "open-to-closed" movement of Burkholderia cepacia lipase lid has been simulated at the atomic level using a hybrid computational method. The two-stage approach combines path-planning algorithms originating from robotics and molecular mechanics methods. In the first stage, a path-planning approach is used to compute continuous and geometrically feasible pathways between two protein conformational states. Then, an energy minimization procedure using classical molecular mechanics is applied to intermediate conformations in the path. The main advantage of such a combination of methods is that only geometrically feasible solutions are prompted for energy calculation in explicit solvent, which allows the atomic-scale description of the transition pathway between two extreme conformations of B. cepacia lipase (BCL; open and closed states) within very short computing times (a few hours on a desktop computer). Of interest, computed pathways enable the description of intermediate conformations along the "open-to-closed" conformational transition of BCL lid and the identification of bottlenecks during the lid closing. Furthermore, consideration of the solvent effect when computing the transition energy profiles provides valuable information regarding the feasibility and the spontaneity of the movement under the influence of the solvent environment. This new hybrid computational method turned out to be well-suited for investigating at an atomistic level large-scale conformational motion and at a qualitative level, the solvent effect on the energy profiles associated with the global motion.