DOI: 10.7554/elife.19274. Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm

Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm

10.7554/elife.19274

Crossref journal-article

eLife Sciences Publications, Ltd

eLife (4374)

Abstract

Biological macromolecules function in highly crowded cellular environments. The structure and dynamics of proteins and nucleic acids are well characterized in vitro, but in vivo crowding effects remain unclear. Using molecular dynamics simulations of a comprehensive atomistic model cytoplasm we found that protein-protein interactions may destabilize native protein structures, whereas metabolite interactions may induce more compact states due to electrostatic screening. Protein-protein interactions also resulted in significant variations in reduced macromolecular diffusion under crowded conditions, while metabolites exhibited significant two-dimensional surface diffusion and altered protein-ligand binding that may reduce the effective concentration of metabolites and ligands in vivo. Metabolic enzymes showed weak non-specific association in cellular environments attributed to solvation and entropic effects. These effects are expected to have broad implications for the in vivo functioning of biomolecules. This work is a first step towards physically realistic in silico whole-cell models that connect molecular with cellular biology.

Bibliography

Yu, I., Mori, T., Ando, T., Harada, R., Jung, J., Sugita, Y., & Feig, M. (2016). Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm. ELife, 5. CLOCKSS.

Authors 7

Isseki Yu (first)
Takaharu Mori (additional)
Tadashi Ando (additional)
Ryuhei Harada (additional)
Jaewoon Jung (additional)
Yuji Sugita (additional)
Michael Feig (additional)

References 56 Referenced 277

10.1073/pnas.1011354107 / PNAS / Crowding and hydrodynamic interactions likely dominate in vivo macromolecular motion by Ando (2010)
10.1002/pol.1958.1203312618 / Journal of Polymer Science / Interaction between particles suspended in solutions of macromolecules by Asakura (1958)
10.1063/1.1571819 / The Journal of Chemical Physics / Accelerated stokesian dynamics: Brownian motion by Banchio (2003)
10.1529/biophysj.104.051078 / Biophysical Journal / Anomalous diffusion of proteins due to molecular crowding by Banks (2005)
10.1038/nchembio.186 / Nature Chemical Biology / Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli by Bennett (2009)
10.1021/ct300400x / Journal of Chemical Theory and Computation / Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles by Best (2012)
10.1146/annurev.fl.20.010188.000551 / Annual Review of Fluid Mechanics / Stokesian dynamics by Brady (1988)
10.1002/jcc.21287 / Journal of Computational Chemistry / CHARMM: the biomolecular simulation program by Brooks (2009)
10.1371/journal.pcbi.1002066 / PLoS Computational Biology / A new view of the bacterial cytosol environment by Cossins (2011)
10.1063/1.464397 / The Journal of Chemical Physics / Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems by Darden (1993)
10.1073/pnas.1006760107 / PNAS / Structure, function, and folding of phosphoglycerate kinase are strongly perturbed by macromolecular crowding by Dhar (2010)
10.1021/bi3000947 / Biochemistry / Weak interactions between folate and osmolytes in solution by Duff (2012)
10.1017/S002211208700171X / Journal of Fluid Mechanics / Dynamic simulation of hydrodynamically interacting particles by Durlofsky (1987)
10.1159/000321499 / Journal of Molecular Microbiology and Biotechnology / Interactions between glycolytic enzymes of Mycoplasma pneumoniae by Dutow (2010)
10.1038/nmeth.1435 / Nature Methods / Protein folding stability and dynamics imaged in a living cell by Ebbinghaus (2010)
10.1063/1.436761 / The Journal of Chemical Physics / Brownian dynamics with hydrodynamic interactions by Ermak (1978)
10.1016/j.jmgm.2015.02.004 / Journal of Molecular Graphics and Modelling / Complete atomistic model of a bacterial cytoplasm for integrating physics, biochemistry, and systems biology by Feig (2015)
10.1016/j.jmgm.2003.12.005 / Journal of Molecular Graphics and Modelling / MMTSB tool set: enhanced sampling and multiscale modeling methods for applications in structural biology by Feig (2004)
10.1021/jp209302e / The Journal of Physical Chemistry B / Variable interactions between protein crowders and biomolecular solutes are important in understanding cellular crowding by Feig (2012)
10.1016/j.jmgm.2013.08.017 / Journal of Molecular Graphics and Modelling / Reaching new levels of realism in modeling biological macromolecules in cellular environments by Feig (2013)
10.1016/S0006-3495(02)75309-5 / Biophysical Journal / Brownian dynamics simulation of rigid particles of arbitrary shape in external fields by Fernandes (2002)
10.1063/1.436725 / The Journal of Chemical Physics / Simulation of polymer dynamics. I. General theory by Fixman (1978)
10.1073/pnas.1201797109 / PNAS / Temperature dependence of protein folding kinetics in living cells by Guo (2012)
10.1021/ja211115q / Journal of the American Chemical Society / Protein crowding affects hydration structure and dynamics by Harada (2012)
10.1021/ja3126992 / Journal of the American Chemical Society / Reduced native state stability in crowded cellular environment due to protein-protein interactions by Harada (2013)
10.1021/ja103166y / Journal of the American Chemical Society / Macromolecular crowding remodels the energy landscape of a protein by favoring a more compact unfolded state by Hong (2010)
10.1016/j.physd.2003.09.016 / Physica D: Nonlinear Phenomena / Time-reversible deterministic thermostats by Hoover (2004)
10.1016/j.jmb.2016.05.024 / Journal of Molecular Biology / Challenges in structural approaches to cell modeling by Im (2016)
10.1063/1.458034 / The Journal of Chemical Physics / A second-order algorithm for the simulation of the Brownian dynamics of macromolecular models by Iniesta (1990)
10.1038/nature07839 / Nature / High-resolution multi-dimensional NMR spectroscopy of proteins in human cells by Inomata (2009)
10.1002/wcms.1220 / Wiley Interdisciplinary Reviews: Computational Molecular Science / GENESIS: a hybrid-parallel and multi-scale molecular dynamics simulator with enhanced sampling algorithms for biomolecular and cellular simulations by Jung (2015)
10.1016/j.cell.2012.05.044 / Cell / A whole-cell computational model predicts phenotype from genotype by Karr (2012)
10.1103/PhysRevLett.110.208102 / Physical Review Letters / Crowding induced entropy-enthalpy compensation in protein association equilibria by Kim (2013)
10.1002/prot.24448 / Proteins / CASP10 results compared to those of previous CASP experiments by Kryshtafovych (2014)
10.1126/science.1176343 / Science / Proteome organization in a genome-reduced bacterium by Kühner (2009)
10.1002/jcc.10272 / Journal of Computational Chemistry / New analytic approximation to the standard molecular volume definition and its application to generalized Born calculations by Lee (2003)
10.1371/journal.pcbi.1000694 / PLoS Computational Biology / Diffusion, crowding & protein stability in a dynamic molecular model of the bacterial cytoplasm by McGuffee (2010)
10.1074/jbc.R100005200 / The Journal of Biological Chemistry / The influence of macromolecular crowding and macromolecular confinement on biochemical reactions in physiological media by Minton (2001)
10.1002/jcc.540130805 / Journal of Computational Chemistry / Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models by Miyamoto (1992)
10.1073/pnas.1417415112 / PNAS / Quinary structure modulates protein stability in cells by Monteith (2015)
10.1128/JB.00284-10 / Journal of Bacteriology / Size dependence of protein diffusion in the cytoplasm of Escherichia coli by Nenninger (2010)
10.1080/00268978400101201 / Molecular Physics / A molecular dynamics method for simulations in the canonical ensemble by Nosé (1984)
10.1371/journal.pcbi.1003638 / PLoS Computational Biology / Are current atomistic force fields accurate enough to study proteins in crowded environments? by Petrov (2014)
10.1002/jcc.20289 / Journal of Computational Chemistry / Scalable molecular dynamics with NAMD by Phillips (2005)
10.1021/jacs.6b06615 / Journal of the American Chemical Society / Coupling and decoupling of rotational and translational diffusion of proteins under crowding conditions by Roos (2016)
10.1073/pnas.1107287108 / PNAS / Protein self-diffusion in crowded solutions by Roosen-Runge (2011)
10.1039/C6CP01056C / Physical Chemistry Chemical Physics / Transient binding accounts for apparent violation of the generalized Stokes-Einstein relation in crowded protein solutions by Rothe (2016)
10.1016/0021-9991(77)90098-5 / Journal of Computational Physics / Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes by Ryckaert (1977)
10.1038/nature07814 / Nature / Protein structure determination in living cells by in-cell NMR spectroscopy by Sakakibara (2009)
10.1016/j.tibs.2005.08.002 / Trends in Biochemical Sciences / Electrochemical structure of the crowded cytoplasm by Spitzer (2005)
10.1016/0968-0004(84)90221-4 / Trends in Biochemical Sciences / Why are enzymes so big? by Srere (1984)
10.1021/jp0666784 / The Journal of Physical Chemistry B / Diffusion and viscosity in a crowded environment: from nano- to macroscale by Szymański (2006)
10.1529/biophysj.107.116236 / Biophysical Journal / Conformational sampling of peptides in cellular environments by Tanizaki (2008)
10.1002/jcc.21367 / Journal of Computational Chemistry / CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields by Vanommeslaeghe (2010)
10.1021/jp0761564 / The Journal of Physical Chemistry B / Evaluating rotational diffusion from protein MD simulations by Wong (2008)
10.1016/0022-2836(91)90499-V / Journal of Molecular Biology / Estimation of macromolecule concentrations and excluded volume effects for the cytoplasm of Escherichia coli by Zimmerman (1991)

Dates

Type	When
Created	8 years, 10 months ago (Oct. 31, 2016, 8 p.m.)
Deposited	1 year, 10 months ago (Oct. 11, 2023, 8:56 p.m.)
Indexed	1 week, 3 days ago (Aug. 26, 2025, 2:36 a.m.)
Issued	8 years, 10 months ago (Nov. 1, 2016)
Published	8 years, 10 months ago (Nov. 1, 2016)
Published Online	8 years, 10 months ago (Nov. 1, 2016)

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BibTeX

@article{Yu_2016, title={Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm}, volume={5}, ISSN={2050-084X}, url={http://dx.doi.org/10.7554/elife.19274}, DOI={10.7554/elife.19274}, journal={eLife}, publisher={eLife Sciences Publications, Ltd}, author={Yu, Isseki and Mori, Takaharu and Ando, Tadashi and Harada, Ryuhei and Jung, Jaewoon and Sugita, Yuji and Feig, Michael}, year={2016}, month=nov }

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