A systems-biology approach to molecular machines: Exploration of alternative transporter mechanisms

Do complex molecular machines tend to exhibit a single mechanism, as suggested in literature and textbook cartoons, or is a multiplicity of pathways possible or even prevalent? Motivated by growing evidence for pathway heterogeneity, we develop theoretical and computational approaches for investigating this question, which could have a significant potential impact in both understanding molecular-scale cell biology and in the design of synthetic machines. Focusing on transport in this initial study, we pursue Monte Carlo exploration of 9model space9. Trial moves adjust transition rates among an automatically generated set of conformational and binding states while maintaining fidelity to thermodynamic principles and fitness goal. The simulations yield both single-mechanism and heterogeneous multi-mechanism models for cotransport in a simple environment. In a 9competitive9 environment with a decoy substrate, several qualitatively distinct models are found which are capable of extremely high discrimination coupled to a leak of the driving ion. The array of functional models would be difficult to find by intuition alone in the complex state-spaces of interest.