There's (still) plenty of room at the bottom.

Motifs, circuits, and networks are core conceptual elements in modern systems and synthetic biology. While there are still undoubtedly more fascinating computations to discover at network level, there are also rich computations that we are only beginning to uncover within the diverse molecules that constitute the networks. Here we explore some work, both new and old, that showcases the incredible computational capacity of seemingly simple molecular mechanisms. A more sophisticated understanding of computations at the molecular level will inspire the development of a more nuanced toolbox for future biological engineering.

[1]  Ankit Gupta,et al.  Antithetic Integral Feedback Ensures Robust Perfect Adaptation in Noisy Biomolecular Networks. , 2014, Cell systems.

[2]  D. Bray.  Molecular Networks: The Top-Down View , 2003, Science.

[3]  F. Narberhaus,et al.  Exploring the modular nature of riboswitches and RNA thermometers , 2016, Nucleic acids research.

[4]  Yuhai Tu,et al.  Modeling the chemotactic response of Escherichia coli to time-varying stimuli , 2008, Proceedings of the National Academy of Sciences.

[5]  Michael B. Elowitz,et al.  An operational view of intercellular signaling pathways , 2017, Current opinion in systems biology.

[6]  Mark E. J. Newman,et al.  The Structure and Function of Complex Networks , 2003, SIAM Rev..

[7]  J. Changeux,et al.  Allosteric proteins and cellular control systems. , 1963, Journal of molecular biology.

[8]  M. Brown,et al.  Mini Review Article , 2022 .

[9]  M. Kirschner,et al.  The role of microtubule dynamics in growth cone motility and axonal growth , 1995, The Journal of cell biology.

[10]  Richard M. Murray,et al.  Feedback Systems An Introduction for Scientists and Engineers , 2007 .

[11]  V. Latora,et al.  Complex networks: Structure and dynamics , 2006 .

[12]  Russell M Gordley,et al.  Modular engineering of cellular signaling proteins and networks. , 2016, Current opinion in structural biology.

[13]  J. Changeux,et al.  Allosteric Mechanisms of Signal Transduction , 2005, Science.

[14]  J. Changeux,et al.  ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL. , 1965, Journal of molecular biology.

[15]  Roman Stocker,et al.  Response rescaling in bacterial chemotaxis , 2011, Proceedings of the National Academy of Sciences.

[16]  R. Feynman.  There's plenty of room at the bottom , 1999 .

[17]  John C. Doyle,et al.  Surviving heat shock: control strategies for robustness and performance. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Monod,et al.  Genetic regulatory mechanisms in the synthesis of proteins. , 1961, Journal of molecular biology.

[19]  Noah Olsman,et al.  Allosteric proteins as logarithmic sensors , 2016, Proceedings of the National Academy of Sciences.

[20]  Richard M. Murray,et al.  Design and Implementation of a Biomolecular Concentration Tracker , 2014, ACS synthetic biology.

[21]  G. Narlikar,et al.  A proposal for kinetic proof reading by ISWI family chromatin remodeling motors. , 2010, Current opinion in chemical biology.

[22]  A. Grossman,et al.  Sigma 32 synthesis can regulate the synthesis of heat shock proteins in Escherichia coli. , 1987, Genes & development.

[23]  U. Alon.  Network motifs: theory and experimental approaches , 2007, Nature Reviews Genetics.

[24]  J. Changeux,et al.  Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation , 2016, Cell.

[25]  M. Paget.  Bacterial Sigma Factors and Anti-Sigma Factors: Structure, Function and Distribution , 2015, Biomolecules.

[26]  R. Unger,et al.  Trade-off between Transcriptome Plasticity and Genome Evolution in Cephalopods , 2017, Cell.

[27]  K. Morris,et al.  The rise of regulatory RNA , 2014, Nature Reviews Genetics.

[28]  L. Peliti,et al.  Thermodynamics of accuracy in kinetic proofreading: dissipation and efficiency trade-offs , 2015, 1504.02494.

[29]  F. Narberhaus,et al.  Molecular basis for temperature sensing by an RNA thermometer , 2006, The EMBO journal.

[30]  Y. Kyōgoku,et al.  Translational induction of heat shock transcription factor sigma32: evidence for a built-in RNA thermosensor. , 1999, Genes & development.

[31]  R. Nussinov,et al.  Is allostery an intrinsic property of all dynamic proteins? , 2004, Proteins.

[32]  T. McKeithan,et al.  Kinetic proofreading in T-cell receptor signal transduction. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[33]  U. Alon,et al.  The incoherent feedforward loop can provide fold-change detection in gene regulation. , 2009, Molecular cell.

[34]  P. Kapranov,et al.  Identification of novel non‐coding RNA‐based negative feedback regulating the expression of the oncogenic transcription factor GLI1 , 2014, Molecular oncology.

[35]  H. Schiessel,et al.  Kinetic proofreading in chromatin remodeling: the case of ISWI/ACF. , 2011, Biophysical journal.

[36]  John Doyle,et al.  Module-Based Analysis of Robustness Tradeoffs in the Heat Shock Response System , 2006, PLoS Comput. Biol..

[37]  J. Hopfield.  Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Straight,et al.  Histone titration against the genome sets the DNA-to-cytoplasm threshold for the Xenopus midblastula transition , 2015, Proceedings of the National Academy of Sciences.

[39]  Jeffrey P. Nguyen,et al.  Rod-like bacterial shape is maintained by feedback between cell curvature and cytoskeletal localization , 2014, Proceedings of the National Academy of Sciences.

[40]  Takashi Yura,et al.  Convergence of Molecular, Modeling, and Systems Approaches for an Understanding of the Escherichia coli Heat Shock Response , 2008, Microbiology and Molecular Biology Reviews.

[41]  H. Wong.  Endogenous Cytoprotective Mechanisms , 2009 .

[42]  Eduardo Sontag,et al.  Fold-change detection and scalar symmetry of sensory input fields , 2010, Proceedings of the National Academy of Sciences.