KEYWORDS Protein flexibility, large-amplitude conformational transitions, elastic network normal mode analysis, path planning algorithms, adenylate kinase open-closed transition pathway. ABSTRACT This paper presents a new method for computing macromolecular motions based on the combination of path planning algorithms, originating from robotics research, and elastic network normal mode analysis. The low-frequency normal modes are regarded as the collective degrees of freedom of the molecule. Geometric path planning algorithms are used to explore these collective degrees of freedom in order to find possible large-amplitude conformational changes. To overcome the limits of the harmonic approximation, which is valid in the vicinity of the minimum energy structure, and to get larger conformational changes, normal mode calculations are iterated during the exploration. Initial results show the efficiency of our method, which requires a small number of normal mode calculations to compute large-amplitude conformational transitions in proteins. A detailed analysis is presented for the computed transition between the open and closed structures of adenylate kinase. This transition, important for its biological function, involves large-amplitude domain motions. The obtained motion correlates well with results presented in related works.