Publications by authors named "Daniel P Aalberts"

12 Publications

  • Page 1 of 1

The new strategies to overcome challenges in protein production in bacteria.

Microb Biotechnol 2019 01 28;12(1):44-47. Epub 2018 Nov 28.

Institut de Biologie Physico-Chimique, Sorbonne Paris Cité, UMR 8261 CNRS-University Paris Diderot, 13 rue Pierre et Marie Curie, 75005, Paris, France.

Recombinant proteins are essential for biotechnology. Here we review some of the key points for improving the production of heterologous proteins, and what can be the future of the field.
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http://dx.doi.org/10.1111/1751-7915.13338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302713PMC
January 2019

Codon Clarity or Conundrum?

Cell Syst 2017 01;4(1):16-19

Department of Biological Sciences, Columbia University, New York, NY 10024, USA. Electronic address:

Synonymous variations in protein-coding sequences alter protein expression dynamics, which has important implications for cellular physiology and evolutionary fitness, but disentangling the underlying molecular mechanisms remains challenging.
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http://dx.doi.org/10.1016/j.cels.2017.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318996PMC
January 2017

Codon influence on protein expression in E. coli correlates with mRNA levels.

Nature 2016 Jan 13;529(7586):358-363. Epub 2016 Jan 13.

Department of Biological Sciences, 702A Fairchild Center, MC2434, Columbia University, New York, NY 10027, USA.

Degeneracy in the genetic code, which enables a single protein to be encoded by a multitude of synonymous gene sequences, has an important role in regulating protein expression, but substantial uncertainty exists concerning the details of this phenomenon. Here we analyse the sequence features influencing protein expression levels in 6,348 experiments using bacteriophage T7 polymerase to synthesize messenger RNA in Escherichia coli. Logistic regression yields a new codon-influence metric that correlates only weakly with genomic codon-usage frequency, but strongly with global physiological protein concentrations and also mRNA concentrations and lifetimes in vivo. Overall, the codon content influences protein expression more strongly than mRNA-folding parameters, although the latter dominate in the initial ~16 codons. Genes redesigned based on our analyses are transcribed with unaltered efficiency but translated with higher efficiency in vitro. The less efficiently translated native sequences show greatly reduced mRNA levels in vivo. Our results suggest that codon content modulates a kinetic competition between protein elongation and mRNA degradation that is a central feature of the physiology and also possibly the regulation of translation in E. coli.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054687PMC
http://dx.doi.org/10.1038/nature16509DOI Listing
January 2016

Free energy cost of stretching mRNA hairpin loops inhibits small RNA binding.

Biophys J 2013 Jan;104(2):482-7

Physics Department, Williams College, Williamstown, Massachusetts, USA.

Small RNA-mRNA binding is an essential step in RNA interference, an important cellular regulatory process. Calculations of binding free energy have been used in binding site prediction, but the cost of stretching the mRNA loop when the small RNA-mRNA duplex forms requires further exploration. Here, using both polymer physics theory and simulations, we estimate the free energy of a stretched mRNA loop. We find loop stretching significantly increases the free energy of 3' supplementary/compensatory miRNA binding and siRNA binding to mRNA hairpin loops. We also make the observation that sites where 3' supplementary binding is available may bind at the seed only, and that loop stretching often favors seed-only binding over seed plus 3' supplementary binding in mRNA hairpins.
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http://dx.doi.org/10.1016/j.bpj.2012.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552280PMC
January 2013

Visualizing RNA base-pairing probabilities with RNAbow diagrams.

RNA 2013 Apr 13;19(4):475-8. Epub 2013 Feb 13.

Department of Physics, Williams College, Williamstown, MA 01267, USA.

There are many effective ways to represent a minimum free energy RNA secondary structure that make it easy to locate its helices and loops. It is a greater challenge to visualize the thermal average probabilities of all folds in a partition function sum; dot plot representations are often puzzling. Therefore, we introduce the RNAbows visualization tool for RNA base pair probabilities. RNAbows represent base pair probabilities with line thickness and shading, yielding intuitive diagrams. RNAbows aid in disentangling incompatible structures, allow comparisons between clusters of folds, highlight differences between wild-type and mutant folds, and are also rather beautiful.
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http://dx.doi.org/10.1261/rna.033365.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677257PMC
April 2013

Loop Entropy Assists Tertiary Order: Loopy Stabilization of Stacking Motifs.

Entropy (Basel) 2011 Nov;13(11):1958-1966

Physics Department, Williams College, Williamstown, MA 01267, USA; Tel.: +1-413-597-3520;

The free energy of an RNA fold is a combination of favorable base pairing and stacking interactions competing with entropic costs of forming loops. Here we show how loop entropy, surprisingly, can promote tertiary order. A general formula for the free energy of forming multibranch and other RNA loops is derived with a polymer-physics based theory. We also derive a formula for the free energy of coaxial stacking in the context of a loop. Simulations support the analytic formulas. The effects of stacking of unpaired bases are also studied with simulations.
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http://dx.doi.org/10.3390/e13111958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569131PMC
November 2011

A two-length-scale polymer theory for RNA loop free energies and helix stacking.

RNA 2010 Jul 26;16(7):1350-5. Epub 2010 May 26.

Department of Physics, Williams College, Williamstown, Massachusetts 01257, USA.

The reliability of RNA secondary structure predictions is subject to the accuracy of the underlying free energy model. Mfold and other RNA folding algorithms are based on the Turner model, whose weakest part is its formulation of loop free energies, particularly for multibranch loops. RNA loops contain single-strand and helix-crossing segments, so we develop an enhanced two-length freely jointed chain theory and revise it for self-avoidance. Our resulting universal formula for RNA loop entropy has fewer parameters than the Turner/Mfold model, and yet simulations show that the standard errors for multibranch loop free energies are reduced by an order of magnitude. We further note that coaxial stacking decreases the effective length of multibranch loops and provides, surprisingly, an entropic stabilization of the ordered configuration in addition to the enthalpic contribution of helix stacking. Our formula is in good agreement with measured hairpin free energies. We find that it also improves the accuracy of folding predictions.
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http://dx.doi.org/10.1261/rna.1831710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885684PMC
July 2010

Quantifying optimal accuracy of local primary sequence bioinformatics methods.

Bioinformatics 2005 Aug 27;21(16):3347-51. Epub 2005 May 27.

Department of Physics, Williams College, Williamstown, MA 01267, USA.

Motivation: Traditional bioinformatics methods scan primary sequences for local patterns. It is important to assess how accurate local primary sequence methods can be.

Results: We study the problem of donor pre-mRNA splice site recognition, where the sequence overlaps between real and decoy datasets can be quantified, exposing the intrinsic limitations of the performance of local primary sequence methods. We assess the accuracy of primary sequence methods generally by studying how they scale with dataset size and demonstrate that our new primary sequence ranking methods have superior performance.
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http://dx.doi.org/10.1093/bioinformatics/bti521DOI Listing
August 2005

Asymmetry in RNA pseudoknots: observation and theory.

Nucleic Acids Res 2005 14;33(7):2210-4. Epub 2005 Apr 14.

Physics Department, Williams College Williamstown, MA 01267, USA.

RNA can fold into a topological structure called a pseudoknot, composed of non-nested double-stranded stems connected by single-stranded loops. Our examination of the PseudoBase database of pseudoknotted RNA structures reveals asymmetries in the stem and loop lengths and provocative composition differences between the loops. By taking into account differences between major and minor grooves of the RNA double helix, we explain much of the asymmetry with a simple polymer physics model and statistical mechanical theory, with only one adjustable parameter.
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http://dx.doi.org/10.1093/nar/gki508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1079967PMC
May 2005

Efficient computation of optimal oligo-RNA binding.

Nucleic Acids Res 2004 17;32(22):6636-42. Epub 2004 Dec 17.

Physics Department, Williams College, Williamstown, MA 01267, USA.

We present an algorithm that calculates the optimal binding conformation and free energy of two RNA molecules, one or both oligomeric. This algorithm has applications to modeling DNA microarrays, RNA splice-site recognitions and other antisense problems. Although other recent algorithms perform the same calculation in time proportional to the sum of the lengths cubed, O((N1 + N2)3), our oligomer binding algorithm, called bindigo, scales as the product of the sequence lengths, O(N1*N2). The algorithm performs well in practice with the aid of a heuristic for large asymmetric loops. To demonstrate its speed and utility, we use bindigo to investigate the binding proclivities of U1 snRNA to mRNA donor splice sites.
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http://dx.doi.org/10.1093/nar/gkh1008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC545450PMC
January 2005

Thermodynamic modeling of donor splice site recognition in pre-mRNA.

Phys Rev E Stat Nonlin Soft Matter Phys 2004 Apr 26;69(4 Pt 1):041903. Epub 2004 Apr 26.

Physics Department, Williams College, Williamstown, Massachusetts 01267, USA.

When eukaryotic genes are edited by the spliceosome, the first step in intron recognition is the binding of a U1 small nuclear RNA with the donor ( 5(') ) splice site. We model this interaction thermodynamically to identify splice sites. Applied to a set of 65 annotated genes, our "finding with binding" method achieves a significant separation between real and false sites. Analyzing binding patterns allows us to discard a large number of decoy sites. Our results improve statistics-based methods for donor site recognition, demonstrating the promise of physical modeling to find functional elements in the genome.
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http://dx.doi.org/10.1103/PhysRevE.69.041903DOI Listing
April 2004

Single-strand stacking free energy from DNA beacon kinetics.

Biophys J 2003 May;84(5):3212-7

Physics Department, Williams College, 33 Lab Campus Drive, Williamstown, MA 01267, USA.

DNA beacons are short single-stranded chains which can form closed hairpin shapes through complementary base pairing at their ends. Contrary to the common polymer theory assumption that only their loop length matters, experiments show that their closing kinetics depend on the loop composition. We have modeled the closing kinetics and in so doing have obtained stacking enthalpies and entropies for single-stranded nucleic acids. The resulting change of persistence length with temperature effects the dynamics. With a Monte Carlo study, we answer another polymer question of how the closing time scales with chain length, finding tau approximately N(2.44+/-0.02). There is a significant crossover for shorter chains, bringing the effective exponent into good agreement with experiment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1302881PMC
http://dx.doi.org/10.1016/S0006-3495(03)70045-9DOI Listing
May 2003
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