Protein Complex Formation: Computational Clarification of the Sequential versus Probabilistic Recruitment Puzzle

Our current view on how protein complexes assemble and disassemble at promoter sites is based on experimental data. For instance this data is provided by biochemical methods (e.g. ChIP-on-chip assays) or GFP-based assays. These two approaches suggest very different characteristics for protein recruitment processes that regulate and initiate gene transcription. Biochemical methods suggest a strictly ordered and consecutive protein recruitment while GFP-based assays draw a picture much closer to chaotic or stochastic recruitment. To understand the reason for these conflicting results, we design a generalized recruitment model (GRM) that allows to simulate all possible scenarios between strictly sequential recruitment and completely probabilistic recruitment. With this model we show that probabilistic, transient binding events that are visible in GFP experiments can not be detected by ChIP experiments. We demonstrate that sequential recruitment processes and probabilistic recruitment processes that contain “shortcuts” exhibit periodic dynamics and are hard to distinguish with standard ChIP measurements. Therefore we propose a simple experimental method that can be used to discriminate sequential from probabilistic recruitment processes. We discuss the limitations of this method.