Abstract
A dynamic model of prokaryotic gene expression is developed that makes considerable use of gene sequence information. The main contribution arises from the fact that the combined gene expression model allows us to access the impact of altering a nucleotide sequence on the dynamics of gene expression rates mechanistically. The high level of detail of the mathematical model is considered as an important step towards bringing together the tremendous amount of biological in-depth knowledge that has been accumulated at the molecular level, using a systems level analysis (in the sense of a bottom-up, inductive approach). This enables to the model to provide highly detailed insights into the various steps of the protein expression process and it allows us to access possible targets for model-based design. Taken as a whole, the mathematical gene expression model presented in this study provides a comprehensive framework for a thorough analysis of sequence-related effects on the stages of mRNA synthesis, mRNA degradation and ribosomal translation, as well as their nonlinear interconnectedness. Therefore, it may be useful in the rational design of recombinant bacterial protein synthesis systems, the modulation of enzyme activities in pathway design, in vitro protein biosynthesis, and RNA-based vaccination.
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Abbreviations
- a i :
-
number of codons representing a particular amino acid i
- A:
-
number of naturally occurring amino acids
- c:
-
codon usage
- C:
-
metabolite concentration (μM)
- d:
-
spacing between ribosomes and degradosomes, and between SD sequence and translational start codons
- D:
-
promoter contained on DNA template
- f:
-
fraction of single-stranded bases within the 23 bases subsequent to the Shine-Dalgarno sequence
- f j,i :
-
relative portion of base j contained in transcript i (%)
- G :
-
free energy (kJ/mol)
- J :
-
number of base triplets of a mRNA
- k i :
-
respective rate constant
- K :
-
last codon of a coding region
- K a :
-
association constant
- K d :
-
dissociation constant
- K I :
-
inhibition constant for respective metabolite (μM)
- K M :
-
Michaelis-Menten constant for respective substrate (μM)
- L j :
-
physical diameter of a ribosome and degradosome, respectively
- m :
-
mass (g)
- m i :
-
ratio of RNA species i to total measured RNA (g/g)
- m i,j :
-
element of matrix M
- m j :
-
reference state of a ribosome and a degradosome, respectively
- M :
-
mRNA
- M :
-
number of mRNA molecules
- M :
-
mRNA matrix
- n :
-
number
- n i :
-
transcript length for RNA species i (kb)
- n cod :
-
number of base triplets used to denote a state
- N :
-
number of ribonucleic bases
- N A :
-
Avogadro number
- R :
-
number of RNA species synthesized from a given DNA template
- S :
-
number of segments
- t :
-
time (min)
- T :
-
number of tRNA species
- T :
-
temperature (K)
- T :
-
time (s)
- V :
-
reaction rate (μM/min)
- V :
-
volume (μl)
- V P :
-
relative protein expression rate (%)
- X :
-
measured radioactivity (dpm/μL)
- z :
-
position of endonucleolytic cleavage site
- Z :
-
number of fragments of a mRNA obtained by endonucleolytic cleavage
- η:
-
fractional codon usage
- μ:
-
specific growth rate (h−1)
- Φ:
-
efficiency factor
- ϕ:
-
T7 transcription terminator
- ϕ10:
-
T7 promoter
- φ:
-
energy charge
- aq:
-
aqueous
- avg:
-
average
- cell:
-
referring to a single cell
- CR:
-
catabolite repression
- d:
-
degradation
- D:
-
refers to promoter sequence of a DNA
- D0:
-
refers to a degradosome association site
- dto:
-
ditto
- eff:
-
effective
- eq:
-
thermodynamic equilibrium
- exp:
-
experimentally determined
- f:
-
formyl-
- f:
-
forward reaction
- i :
-
count index
- in:
-
entering equilibrium computation
- I:
-
induction
- j :
-
count index
- k :
-
count index
- m:
-
methionine
- NTP:
-
nucleoside triphosphate
- out:
-
outcome of equilibrium computation
- qss:
-
quasi-stationary state
- r:
-
reverse reaction
- R0:
-
refers to a ribosome binding site
- s :
-
count index
- sim:
-
predicted from simulation
- t:
-
denotes total concentration
- un:
-
unbound
- ′:
-
refers to new codon grid representation
- 0:
-
initial condition
- 0:
-
standard condition
- A:
-
refers to the A-site of a ribosome
- D:
-
degradosome
- M:
-
mRNA
- M:
-
methionine
- max:
-
maximum value
- P:
-
refers to the P-site of a ribosome
- R:
-
ribosome
- R* :
-
ribosome bound to the initiation codon prior to IF2-dissociation
- 30S:
-
small prokaryotic ribosomal subunit
- 30SIC:
-
30S initiation complex
- 50S:
-
large prokaryotic ribosomal subunit
- 70S:
-
free, undissociated prokaryotic ribosome
- 70SIC:
-
70S initiation complex
- A:
-
adenine
- aa:
-
amino acid(s)
- aa-tRNA:
-
aminoacyl-tRNA
- Ac:
-
acetate
- Ack:
-
acetate kinase
- AcP:
-
acetyl phosphate
- ACSL:
-
Advanced Continuous Simulation Language
- Adk:
-
adenylate kinase
- ADP:
-
adenosine diphosphate
- Ala:
-
alanine
- AMP:
-
adenosine monophosphate
- Arg:
-
arginine
- ARS:
-
aminoacyl-tRNA-synthetase
- Asn:
-
asparagine
- Asp:
-
aspartic acid
- ass:
-
association
- ATP:
-
adenosine triphosphate
- AUG:
-
translational start codon
- bp:
-
base pairs
- BSA:
-
bovine serum albumin
- C:
-
cytosine
- CDP:
-
cytosine diphosphate
- CMP:
-
cytosine monophosphate
- CTP:
-
cytosine triphosphate
- Cys:
-
cysteine
- DNA:
-
deoxyribonucleic acid
- E:
-
enzyme
- EC:
-
Enzyme Commission
- EF:
-
translational elongation factor
- EMBL:
-
European Molecular Biology Laboratory
- endo:
-
endonucleolytic
- exo:
-
exonucleolytic
- F:
-
folded conformation of the ribosome binding site
- fMet-tRNA f M :
-
N-formylmethionyl-tRNA
- Frag:
-
mRNA fragment
- G:
-
guanine
- GDP:
-
guanosine diphosphate
- GFP:
-
green fluorescent protein
- Gln:
-
glutamine
- Glu:
-
glutamic acid
- Gly:
-
glycine
- GMP:
-
guanosine monophosphate
- GTP:
-
guanosine triphosphate
- h:
-
hour
- His:
-
histidine
- IC:
-
initiation complex
- IF:
-
translational initiation factor
- IF2D:
-
IF2-dependent GTP hydrolysis
- Ile:
-
isoleucine
- K:
-
Kelvin
- kb:
-
kilobases
- kDa:
-
kiloDalton (1 Da ≙ 1 g/mol)
- kJ:
-
kiloJoule
- Leu:
-
leucine
- Lys:
-
lysine
- Met:
-
methionine
- min:
-
minute
- mRNA:
-
messenger RNA
- mv:
-
degradosome movement
- Ndk:
-
nucleoside diphosphate kinase
- NDP:
-
nucleoside diphosphate
- Nmk:
-
nucleoside monophosphate kinase
- NMP:
-
nucleoside monophosphate
- nt:
-
nucleotide(s)
- NTP:
-
nucleoside triphosphate
- P:
-
promoter
- PAGE:
-
polyacryl amide gel electrophoresis
- PAP I:
-
poly-adenylate phosphorylase
- pelB:
-
pelB leader sequence
- Phe:
-
phenylalanine
- Pi:
-
inorganic phosphate
- PNPase:
-
polynucleotide phosphorylase
- PPi:
-
inorganic pyrophosphate
- PPK:
-
polyphosphate kinase
- Pro:
-
proline
- RBS:
-
ribosome binding site
- rDNA:
-
recombinant DNA
- RF:
-
translational termination factor
- RFH:
-
a particular translational termination factor
- RNA:
-
ribonucleic acid
- RNAP:
-
DNA-dependent RNA polymerase
- RNase:
-
ribonuclease
- RP:
-
ribosomal protein
- RRF:
-
ribosome release factor
- rRNA:
-
ribosomal RNA
- s:
-
second
- S1:
-
ribosomal protein S1 (contained in 30S ribosomal subunit)
- Ser:
-
serine
- SNP:
-
single-nucleotide polymorphism
- ssRNA:
-
single-stranded RNA
- T:
-
terminator
- T:
-
thymine
- T:
-
tRNA
- T3:
-
ternary complex (consists of one copy of EFTu, GTP, and aa-tRNA)
- TC:
-
transcription
- TCA:
-
tricarboxylic acid
- TCE:
-
transcription elongation
- TCI:
-
transcription initiation
- TCT:
-
transcription termination
- TE:
-
termination efficiency
- THF:
-
H4-folate
- Thr:
-
threonine
- TL:
-
translation
- TLE:
-
translation elongation
- TLI:
-
translation initiation
- TLT:
-
translation termination
- tmRNA:
-
transfer-messenger RNA
- Tris:
-
tris(hydroxymethyl)aminomethane
- tRNA:
-
transfer RNA
- Trp:
-
tryptophan
- Tyr:
-
tyrosine
- U:
-
unit
- U:
-
uracil
- UDP:
-
uracil diphosphate
- UMP:
-
uracil monophosphate
- UTP:
-
uracil triphosphate
- Val:
-
valine
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Arnold, S., Siemann-Herzberg, M., Schmid, J., Reuss, M. Model-based Inference of Gene Expression Dynamics from Sequence Information. In: Nielsen, J. (eds) Biotechnology for the Future. Advances in Biochemical Engineering/Biotechnology, vol 100. Springer, Berlin, Heidelberg. https://doi.org/10.1007/b136414
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