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

PLoS Comput Biol. 2020 Jul 2;16(7):e1007884. doi: 10.1371/journal.pcbi.1007884. eCollection 2020 Jul.

Abstract

Motivated by growing evidence for pathway heterogeneity and alternative functions of molecular machines, we demonstrate a computational approach for investigating two questions: (1) Are there multiple mechanisms (state-space pathways) by which a machine can perform a given function, such as cotransport across a membrane? (2) How can additional functionality, such as proofreading/error-correction, be built into machine function using standard biochemical processes? Answers to these questions will aid both the understanding of molecular-scale cell biology and the design of synthetic machines. Focusing on transport in this initial study, we sample a variety of mechanisms by employing Metropolis Markov chain Monte Carlo. Trial moves adjust transition rates among an automatically generated set of conformational and binding states while maintaining fidelity to thermodynamic principles and a user-supplied fitness/functionality goal. Each accepted move generates a new model. The simulations yield both single and mixed reaction pathways for cotransport in a simple environment with a single substrate along with a driving ion. In a "competitive" environment including an additional decoy substrate, several qualitatively distinct reaction pathways are found which are capable of extremely high discrimination coupled to a leak of the driving ion, akin to proofreading. The array of functional models would be difficult to find by intuition alone in the complex state-spaces of interest.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Biological Transport / physiology*
  • Computer Simulation*
  • Computers, Molecular*
  • Markov Chains
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / metabolism
  • Monte Carlo Method
  • Systems Biology / methods*
  • Thermodynamics

Substances

  • Membrane Transport Proteins