Computational Analyses of Synergism in Small Molecular Network Motifs

Cellular functions and responses to stimuli are controlled by complex regulatory networks that comprise a large diversity of molecular components and their interactions. However, achieving an intuitive understanding of the dynamical properties and responses to stimuli of these networks is hampered by their large scale and complexity. To address this issue, analyses of regulatory networks often focus on reduced models that depict distinct, reoccurring connectivity patterns referred to as motifs. Previous modeling studies have begun to characterize the dynamics of small motifs, and to describe ways in which variations in parameters affect their responses to stimuli. The present study investigates how variations in pairs of parameters affect responses in a series of ten common network motifs, identifying concurrent variations that act synergistically (or antagonistically) to alter the responses of the motifs to stimuli. Synergism (or antagonism) was quantified using degrees of nonlinear blending and additive synergism. Simulations identified concurrent variations that maximized synergism, and examined the ways in which it was affected by stimulus protocols and the architecture of a motif. Only a subset of architectures exhibited synergism following paired changes in parameters. The approach was then applied to a model describing interlocked feedback loops governing the synthesis of the CREB1 and CREB2 transcription factors. The effects of motifs on synergism for this biologically realistic model were consistent with those for the abstract models of single motifs. These results have implications for the rational design of combination drug therapies with the potential for synergistic interactions.Author Summary: Cellular responses to stimuli are controlled by complex regulatory networks that comprise many molecular components. Understanding such networks is critical for understanding normal cellular functions and pathological conditions. Because the complexity of these networks often precludes intuitive insights, a useful approach is to study mathematical models of small network motifs having reduced complexity yet consisting of key regulatory components of the more complex networks. Computational studies have analyzed the behavior of small motifs, and have begun to describe the ways in which variations in parameters affect their functional properties. Here, we investigated how variations in pairs of parameters act synergistically (or antagonistically) to alter responses of ten common network motifs. Simulations identified parameter variations that maximized synergism, and examined the ways in which synergism was affected by stimulus protocols and motif architecture. The results have implications for the rational design of combination drug therapies where a goal is to identify drugs that when administered together have a greater effect than would be predicted by simple addition of single-drug effects (i.e., super-additive effects), thereby allowing for lower drug doses, minimizing undesirable effects.