Reduced alphabet of prebiotic amino acids optimally encodes the conformational space of diverse extant protein folds

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

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Faculty Opinions recommendation of Simplified protein design biased for prebiotic amino acids yields a foldable, halophilic protein.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718002942.793475498 ◽

2013 ◽

Author(s):

Javier Sancho

Keyword(s):

Amino Acids ◽

Protein Design ◽

Prebiotic Amino Acids

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Structural analysis of point mutations at theVaccinia virusA20/D4 interface

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x16011778 ◽

2016 ◽

Vol 72 (9) ◽

pp. 687-691 ◽

Cited By ~ 4

Author(s):

Céline Contesto-Richefeu ◽

Nicolas Tarbouriech ◽

Xavier Brazzolotto ◽

Wim P. Burmeister ◽

Christophe N. Peyrefitte ◽

...

Keyword(s):

Crystal Structure ◽

Amino Acids ◽

Structural Analysis ◽

Complex Formation ◽

Dna Polymerase ◽

Point Mutations ◽

Conformational Space ◽

Uracil Dna Glycosylase ◽

Dimerization Interface ◽

Solvation Parameters

TheVaccinia viruspolymerase holoenzyme is composed of three subunits: E9, the catalytic DNA polymerase subunit; D4, a uracil-DNA glycosylase; and A20, a protein with no known enzymatic activity. The D4/A20 heterodimer is the DNA polymerase cofactor, the function of which is essential for processive DNA synthesis. The recent crystal structure of D4 bound to the first 50 amino acids of A20 (D4/A201–50) revealed the importance of three residues, forming a cation–π interaction at the dimerization interface, for complex formation. These are Arg167 and Pro173 of D4 and Trp43 of A20. Here, the crystal structures of the three mutants D4-R167A/A201–50, D4-P173G/A201–50and D4/A201–50-W43A are presented. The D4/A20 interface of the three structures has been analysed for atomic solvation parameters and cation–π interactions. This study confirms previous biochemical data and also points out the importance for stability of the restrained conformational space of Pro173. Moreover, these new structures will be useful for the design and rational improvement of known molecules targeting the D4/A20 interface.

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Formaldehyde and Ammonia as Precursors to Prebiotic Amino Acids

Science ◽

10.1126/science.174.4013.1039 ◽

1971 ◽

Vol 174 (4013) ◽

pp. 1039-1040

Author(s):

Y. Wolman ◽

Stanley L. Miller ◽

J. Ibanez ◽

J. Oró

Keyword(s):

Amino Acids ◽

Prebiotic Amino Acids

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Prebiotic amino acids bind to and stabilize prebiotic fatty acid membranes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1900275116 ◽

2019 ◽

Vol 116 (35) ◽

pp. 17239-17244 ◽

Cited By ~ 15

Author(s):

Caitlin E. Cornell ◽

Roy A. Black ◽

Mengjun Xue ◽

Helen E. Litz ◽

Andrew Ramsay ◽

...

Keyword(s):

Amino Acids ◽

Fatty Acid ◽

Divalent Cations ◽

Building Blocks ◽

Rna Catalysis ◽

Membrane Stabilization ◽

Molecular Building Blocks ◽

Prebiotic Amino Acids ◽

Self Assembled ◽

High Concentrations

The membranes of the first protocells on the early Earth were likely self-assembled from fatty acids. A major challenge in understanding how protocells could have arisen and withstood changes in their environment is that fatty acid membranes are unstable in solutions containing high concentrations of salt (such as would have been prevalent in early oceans) or divalent cations (which would have been required for RNA catalysis). To test whether the inclusion of amino acids addresses this problem, we coupled direct techniques of cryoelectron microscopy and fluorescence microscopy with techniques of NMR spectroscopy, centrifuge filtration assays, and turbidity measurements. We find that a set of unmodified, prebiotic amino acids binds to prebiotic fatty acid membranes and that a subset stabilizes membranes in the presence of salt and Mg2+. Furthermore, we find that final concentrations of the amino acids need not be high to cause these effects; membrane stabilization persists after dilution as would have occurred during the rehydration of dried or partially dried pools. In addition to providing a means to stabilize protocell membranes, our results address the challenge of explaining how proteins could have become colocalized with membranes. Amino acids are the building blocks of proteins, and our results are consistent with a positive feedback loop in which amino acids bound to self-assembled fatty acid membranes, resulting in membrane stabilization and leading to more binding in turn. High local concentrations of molecular building blocks at the surface of fatty acid membranes may have aided the eventual formation of proteins.

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Prebiotic Amino Acids as Asymmetric Catalysts

Science ◽

10.1126/science.1093057 ◽

2004 ◽

Vol 303 (5661) ◽

pp. 1151-1151 ◽

Cited By ~ 253

Author(s):

S. Pizzarello

Keyword(s):

Amino Acids ◽

Asymmetric Catalysts ◽

Prebiotic Amino Acids

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Homochirality May Not Be a Prerequisite for Protein Structure and Function: A Computational Model Investigation of Prebiotic Peptides

10.20944/preprints202003.0005.v1 ◽

2020 ◽

Author(s):

Jianxun Shen ◽

Pauline M. Schwartz ◽

Carl Barratt

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Hierarchical Cluster ◽

Building Blocks ◽

Beta Sheets ◽

Folding Energy ◽

Primitive Earth ◽

C Terminus ◽

Significant Difference ◽

Prebiotic Amino Acids

On the primitive Earth, both L- and D-amino acids would have been present. However, only L-amino acids are essential blocks to construct proteins in modern life. To study the relative stability of homochiral and heterochiral peptides, a variety of computational methods were employed. 10 prebiotic amino acids (Gly, Ala, Asp, Glu, Ile, Leu, Pro, Ser, Thr, and Val) were previously determined by multiple previous meteorite, spark discharge, and hydrothermal vent studies. We focused on what had been reported as primary early Earth polypeptide analogs: 1ARK, 1PPT, 1ZFI, and 2LZE. Tripeptide composed of only Asp, Ser, and Val exemplified that different positions (i.e., N-terminus, C-terminus, and middle) made a difference in minimal folding energy of peptides, while the classification of amino acid (hydrophobic, acidic, or hydroxylic) did not show significant difference. Hierarchical cluster analysis for dipeptides with all possible combinations of the proposed 10 prebiotic amino acids and their D-amino acid substituted derivatives generated five clusters. Prebiotic polypeptides were built up to test the significance of molecular fluctuations, secondary structure occupancies, and folding energy differences based on these clusters. Most interestingly, among 129 residues, mutation sensitivity profiles presented that the ratio of more stable to less stable to equally stable D-amino acids was about 1:1:1. In conclusion, some combinations of a mixture of L- and D-amino acids can act as essential building blocks of life. Peptides with α-helices, long β-sheets, and long loops are usually less sensitive to D-amino acid replacements in comparison to short β-sheets.

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