title: solveME: fast and reliable solution of nonlinear ME models.
abstract: BACKGROUND
  Genome-scale models of metabolism and macromolecular expression (ME) significantly expand the scope and predictive capabilities of constraint-based modeling. ME models present considerable computational challenges: they are much (>30 times) larger than corresponding metabolic reconstructions (M models), are multiscale, and growth maximization is a nonlinear programming (NLP) problem, mainly due to macromolecule dilution constraints.
  
  
  RESULTS
  Here, we address these computational challenges. We develop a fast and numerically reliable solution method for growth maximization in ME models using a quad-precision NLP solver (Quad MINOS). Our method was up to 45 % faster than binary search for six significant digits in growth rate. We also develop a fast, quad-precision flux variability analysis that is accelerated (up to 60× speedup) via solver warm-starts. Finally, we employ the tools developed to investigate growth-coupled succinate overproduction, accounting for proteome constraints.
  
  
  CONCLUSIONS
  Just as genome-scale metabolic reconstructions have become an invaluable tool for computational and systems biologists, we anticipate that these fast and numerically reliable ME solution methods will accelerate the wide-spread adoption of ME models for researchers in these fields.
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, 92093, CA, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Management Science and Engineering, Stanford University, Stanford, 94305, CA, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, 92093, CA, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Ebrahim
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, 92093, CA, USA.
authors.forename: Colton J
authors.initials: CJ
authors.lastname: Lloyd
authors.affiliation: Department of Management Science and Engineering, Stanford University, Stanford, 94305, CA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Saunders
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, 92093, CA, USA. palsson@ucsd.edu.|Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet, Building 220, Kongens Lyngby, DK-2800, Denmark. palsson@ucsd.edu.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Palsson
keywords: Constraint-based modeling; Metabolism; Nonlinear optimization; Proteome; Quasiconvex