Protein–protein association can frequently involve significant backbone conformational changes of the protein partners. A computationally rapid method has been developed that allows to approximately account for global conformational changes during systematic protein–protein docking starting from many thousands of start configurations. The approach employs precalculated collective degrees of freedom as additional variables during protein–protein docking minimization. The global collective degrees of freedom are obtained from normal mode analysis using a Gaussian network model for the protein. Systematic docking searches were performed on 10 test systems that differed in the degree of conformational change associated with complex formation and in the degree of overlap between observed conformational changes and precalculated flexible degrees of freedom. The results indicate that in case of docking searches that minimize the influence of local side chain conformational changes inclusion of global flexibility can significantly improve the agreement of the near-native docking solutions with the corresponding experimental structures. For docking of unbound protein partners in several cases an improved ranking of near native docking solutions was observed. This was achieved at a very modest (∼2-fold) increase of computational demands compared to rigid docking. For several test cases the number of docking solutions close to experiment was also significantly enhanced upon inclusion of soft collective degrees of freedom. This result indicates that inclusion of global flexibility can facilitate in silico protein–protein association such that a greater number of different start configurations results in favorable complex formation. Proteins 2008. © 2007 Wiley-Liss, Inc.