Article, Biochemistry|April 2022

Language As a Source of Novel Bioactive Peptides: Peptide SVENSKAAKADEMIEN

Current Bioscience. 2022;2(2):e01

DOI: https://doi.org/10.51959/cb.2022.v2n2.e01

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Wade, D. (2022). Language As a Source of Novel Bioactive Peptides: Peptide SVENSKAAKADEMIEN. Current Bioscience, 2(2), e01 https://doi.org/10.51959/cb.2022.v2n2.e01

* Wade Research Foundation, Princeton, New Jersey, USA

^ Corresponding author: David Wade, wade-research@hotmail.com

Abstract

Most peptides have been discovered from natural sources or via combinatorial chemistry methods, but the International Union of Pure and Applied Chemistry’s one-letter symbolism for the names of amino acids facilitates the use of language as a novel source of potentially bioactive peptides.  Any word, name, or phrase composed of 21 letters of the 26-letter English (or French, German, Spanish, or Swedish) alphabet can be viewed as not only a sequence of letters, but also as a sequence of unambiguous symbols for the names of amino acids (i.e., a peptide).  Protein database searches reveal that is sometimes possible to find such name peptides within the larger sequences of known proteins, but most are novel.  Peptides designed using this name-to-peptide method have been chemically synthesized, subjected to laboratory testing, and found to exhibit potentially useful biomedical properties.  This article describes research in the new field of name peptides, including a theoretical analysis of a peptide based on the name of the Swedish Academy, the organization that selects recipients of the Nobel Prize in Literature.

 

Keywords: Peptide, nobel peptide, combinatorial chemistry methods, amino acid, name-to-peptide method..

 

Introduction

Amino acids, peptides, proteins, and the IUPAC nomenclature.

Polypeptides are polymers of amino acids (AAs) linked by amide, or peptide, bonds (Fig. 1) [1].  Polypeptides containing less than 100 AAs are referred to as peptides, and those containing more than 100 AAs are called proteins.  A well-known peptide is insulin, a hormone that is involved in carbohydrate and lipid metabolism, and that is used in the treatment of diabetes [2].  The human form of insulin contains 51 AAs.

Etc.-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-Etc.

Fig. 1.  Peptides are polymers of amino acids (O) linked by amide bonds (-).

There are 21 amino acids that are genetically encoded and commonly found in peptides and proteins isolated from natural sources [1].  The International Union of Pure and Applied Chemistry (IUPAC) has developed a nomenclature for AAs that includes trivial and systematic names, 3-letter abbreviations of trivial names, and 1-letter symbols for AA names (Table 1) [3].  Note that the word, letter, here refers to letters of the 26-letter English alphabet, but it could also refer to the same letters found in, for example, the French, German, Spanish, and Swedish alphabets [4].  Twenty-one of the 26 IUPAC 1-letter symbols are unambiguous symbols for AA names, but 3 letters have ambiguous assignments (i.e., B, X, and Z) and 2 letters have no assignments (i.e., J and O).  Descriptions of the AA compositions and sequences of peptides and proteins can be quite cumbersome when using the trivial or systematic names.  Consequently, the 3-letter abbreviations and 1-letter symbols are the methods used most often in scientific publications to represent AA sequences, and 1-letter symbols are the method used to store the AA sequences of 467,912,207 proteins (as of April 16, 2022) in the nonredundant protein sequence database of the US National Center for Biotechnology Information (NCBI) [5].

A new source of peptides.

Although undoubtedly unintentional, the decision of the IUPAC, to use single letters of the English alphabet as symbols for the names of AAs, had the side effect of creating a new and very large source of peptides.  Most bioactive peptides have been obtained from natural sources, or through combinatorial chemistry [6], but the new source of peptides is based on language rather than nature.  Strings of English alphabet letters, such as found in names, words, phrases, and sentences, can also be viewed as strings of AAs, or peptides.  For example, the English, French, German, Spanish, and Swedish dictionaries contain a total of about 1,685,000 words (470,000 English, 135,000 French, 330,000 German, 150,000 Spanish, and 600,000 Swedish words) [7], a substantial portion of which are compatible with unambiguous IUPAC 1-letter symbols for AA names and could represent “word peptides”.

Another large source of language-based peptides are names, personal or otherwise.  All cultures place a special emphasis on personal names, which are nothing more than sequences of letters [8-12].  In the business world, company and brand names are considered so important that they are trademarked [13].  Consequently, names also can be considered a reservoir of novel peptides (i.e., name peptides).

Finally, since peptides contain less than 100 amino acids, it is also possible that phrases and short sentences, containing less than 100 letters, could also be considered as peptides.  For example, the English phrase, “Happy as a clam at high tide.” [14], contains 22 letters, all of which are compatible with the unambiguous IUPAC symbols for the names of amino acids.  If the spaces between words are eliminated, this phrase could be the basis for creation of the 22 amino acid peptide, HAPPYASACLAMATHIGHTIDE.

Names, words, and phrases that are composed of the letters of the English (or French, German, Spanish, or German) alphabets may occur as peptides in nature, and this possibility can be tested by subjecting the name, word, or phrase to a BLAST search [15] of the NCBI nonredundant protein database.  It is often possible to find such names, words, and phrases as portions of larger proteins in the database, and sometimes in great abundance (i.e., greater than 5,000 occurrences).

Methods and Results

Conversion of a name to a name peptide

As an example of the name-to-peptide method, the Swedish name of the Swedish Academy, Svenska Akademien, was chosen for theoretical analysis.  According to its website, “The Swedish Academy is an independent cultural institution, founded in 1786 by King Gustaf III in order to advance the Swedish language and Swedish literature. The Academy has also awarded the Nobel Prize in Literature since 1901.” [16]. The first step of the name-to-peptide method is to remove any spaces, punctuation marks, or symbols from the name that are not compatible with the 21 unambiguous IUPAC symbols for the names of AAs.  Therefore, Svenska Akademien becomes SVENSKAAKADEMIEN, which is shown in all capital letters to further emphasize that the sequence now represents AAs.

Table 1. IUPAC names and 1-letter symbols for the 21 genetically encoded amino acids commonly found in natural proteins [3]. The name peptide (NP) symbols, and English (E) alphabet letters are shown for comparison purposes. The name-to-peptide method uses only the 21 unambiguous IUPAC 1-letter symbols.
IUPAC1 
Trivial name Systematic name 1-letter

symbol

 NP E
Alanine 2-Aminopropanoic acid A A A
Asparagine or Aspartic acid 2-Amino-3-carbamoylpropanoic acid or 2-Aminobutanedioic acid B1 B
Cysteine 2-Amino-3-mercaptopropanoic acid C C C
Aspartic acid 2-Aminobutanedioic acid D D D
Glutamic acid 2-Aminopentanedioic acid E E E
Phenylalanine 2-Amino-3-phenylpropanoic acid F F F
Glycine Aminoethanoic acid G G G
Histidine 2-Amino-3-(1H-imidazol-4-yl)-
propanoic acid		 H H H
Isoleucine 2-Amino-3-methylpentanoic acid I I I
(None) (Not assigned) J1 J
Lysine 2,6-Diaminohexanoic acid K K K
Leucine 2-Amino-4-methylpentanoic acid L L L
Methionine 2-Amino-4-(methylthio)butanoic acid M M M
Asparagine 2-Amino-3-carbamoylpropanoic acid N N N
(None) (Not assigned) O1 O
Proline Pyrrolidine-2-carboxylic acid P P P
Glutamine 2-Amino-4-carbamoylbutanoic acid Q Q Q
Arginine 2-Amino-5-guanidinopentanoic acid R R R
Serine 2-Amino-3-hydroxypropanoic acid S S S
Threonine 2-Amino-3-hydroxybutanoic acid T T T
Selenocysteine 2-Amino-3-selanylpropanoic U U U
Valine 2-Amino-3-methylbutanoic acid V V V
Tryptophan 2-Amino-3-(lH-indol-3-yl)-
propanoic acid		 W W W
(Unspecified amino acid) (Unspecified amino acid) X1 X
Tyrosine 2-Amino-3-(4-hydroxyphenyl)-

propanoic acid

 Y Y Y
Glutamic acid or Glutamine 2-Aminopentanedioic acid or

2-Amino-4-carbamoyl-butanoic acid

 Z1 Z
Note:  1IUPAC 1-letter symbols with ambiguous meanings are: B (Asparagine or Aspartic acid); X (Unspecified amino acid); Z (glutamic acid or glutamine).  Symbols not assigned by the IUPAC are J and O.
Table 2.  Partial results of a BLAST search of the NCBI non-redundant protein database [15], containing 467,912,207 protein sequences (as of April 16, 2022), for the amino acid sequence SVENSKAAKADEMIEN.
Sequence Found  Percent 

Identity 

 Protein  Organism  Sequence ID  Location in protein AA sequence 
SVENS_AAKAD_____ 62% 4Fe-4S dicluster domain-containing protein Planctomycetaceae bacterium HIF34834.1 665-675/682
____SKAAKADEM___ 56% PREDICTED: uncharacterized protein LOC104878608 Vitis vinifera XP_010647494.1 67-75/203
_____KAAKADEMI__ 56% Holliday junction branch migration protein RuvA Candidatus Pullichristensenella excrementipullorum HIV30448.1 179-187/196
______AAK__EMIEN 50% KIF3A isoform 7, partial Pan troglodytes PNI50057.1 83-92/185

Determining if the name peptide occurs in nature

The next step is to determine if peptide SVENSKAAKADEMIEN has been found in nature.  This was done by doing a BLAST search of the NCBI’s nonredundant protein sequence database.  Although the complete sequence was not found, portions of the sequence were found within the larger AA sequences of several proteins (Table 2).  The sequences found in the database covered all segments of the search sequence, with some having 62% identity with the search sequence.  These results indicated that peptide SVENSKAAKADEMIEN is novel, and that its AA sequence is compatible with natural proteins.

Physical properties and molecular modeling of peptide SVENSKAAKADEMIEN

Some physical properties of peptide SVENSKAAKADEMIEN were determined and are shown in Table 3. There are two types of secondary structural extremes that are commonly found in proteins, the ß-strand and the α-helix (Fig. 2).  It could reasonably be expected that peptide SVENSKAAKADEMIEN might form either of these structures, or some combination of the two, upon interactions with other biomolecules, such as proteins.  Consequently, peptide SVENSKAAKADEMIEN was modeled in both structural extremes and the results are shown in Figures 3-6.

Peptide SVENSKAAKADEMIEN as a potential antiviral compound

Any biological activities of peptide SVENSKAAKADEMIEN would probably be a result of its interactions with other biomolecules, such as proteins.  The potential usefulness of peptide SVENSKAAKADEMIEN was explored by considering it as a potential inhibitor of the interaction between the SARS CoV-2 spike glycoprotein and the angiotensin converting enzyme-2 (ACE2) receptor found on the surfaces of lung, heart, artery, kidney, and intestinal cells (Fig. 7).  This interaction is thought to be the first step in the infection of host cells by the SARS CoV-2 virus [20].  The AA residues in both proteins that are involved in the interaction are listed in Table 4.  If peptide SVENSKAAKADEMIEN could bind to the interaction surfaces of either, or both, the SARS CoV-2 spike glycoprotein’s receptor binding domain (RBD) or the ACE2 receptor’s peptidase domain (PD), it might inhibit the virus-host cell interaction.

Table 3. Some physical properties of peptide SVENSKAAKADEMIEN as determined with the ProtParam program [17] and by inspection of the peptide’s AA sequence.
Number of AAs 16
Molecular weight 1735.88
Theoretical pI 4.41
AA composition Alanine (A), 3, 18.8%

Asparagine (N), 2, 12.5%

Aspartic acid (D), 1, 6.2%

Glutamic acid (E), 3, 18.8%

Isoleucine (I), 1, 6.2%

Lysine (K), 2, 12.5%

Methionine (M), 1, 6.2%

Serine (S), 2, 12.5%

Valine (V), 1, 6.2%
Number of negatively charge residues 4
Number of positively charged residues 2
Net charge at pH 71 -2
Formula C70H118N20O29S1
Total number of atoms 238
Estimated half-life2 1.9 hours (mammalian reticulocytes, in vitro)

>20 hours (yeast, in vivo)

>10 hours (Escherichia coli, in vivo)
Instability index3 31.53 (stable)
Aliphatic index4 61.25
Grand average of hydropathicity5 -0.900
Notes: 1The net charge at pH 7 was determined by inspection of the AA sequence (e.g., see molecular models of Figures 2-5). 2A prediction of the time it takes for half of the amount of protein in a cell to disappear after its synthesis in the cell. 3An estimate of the stability of the peptide in a test tube. 4The relative volume occupied by aliphatic side chains (Alanine, Valine, and Isoleucine). 5The sum of hydropathy values of all the AAs, divided by the number of AA residues in the sequence. Positive numbers indicate hydrophobic peptides, and the larger the number, the more hydrophobic the peptide. Negative numbers indicate hydrophilic peptides, and the larger the negative number, the more hydrophilic the peptide.

To test this possibility, peptide SVENSKAAKADEMIEN, as an α-helix, was docked to (1) the crystal structure of SARS-CoV-2 spike RBD and (2) the ACE2 PD (both PDB 6M0J [20]) using the ClusPro 2.0 protein-protein docking program [23].  The program generated models based upon four types of forces: balanced, electrostatic-favored, hydrophobic-favored, and van der Waals plus electrostatic, and the results are shown in Tables 5 and 6.  Docking of peptide SVENSKAAKADEMIEN with the SARS CoV-2 spike glycoprotein RBD produced 60 models, 4 of which had the peptide located at the RBD-PD interaction surface.  AA residues involved in the RBD-peptide interactions of these 4 models are noted in Table 5, and the average interatomic distance between AA residues was 2.7-2.8 Å, within the range of hydrogen bonding distances.  In contrast, docking of peptide SVENSKAAKADEMIEN with the ACE2 PD produced 32 models, but none had the peptide located at the RBD-PD interaction surface.  Consequently, it is theoretically possible that the peptide could act as an inhibitor of the virus-host cell interaction, particularly by binding to the SARS CoV-2 spike glycoprotein RBD.

Docking of peptide SVENSKAAKADEMIEN with the SARS CoV-2 spike glycoprotein RBD produced 60 models, 4 of which had the peptide located at the RBD-PD interaction surface.  AA residues involved in the RBD-peptide interactions of these 4 models are noted in Table 5, and the average interatomic distance between AA residues was 2.7-2.8 Å, within the range of hydrogen bonding

Discussion

The example of peptide SVENSKAAKADEMIEN described herein illustrates the general approach used for name peptide design and theoretical analyses. The next steps would be synthesis and testing of the peptide, which may be reported in a future publication.

Table 4.  Nonbonding interactions between the human SARS CoV-2 spike protein receptor binding domain (RBD) and the human ACE-2 peptidase domain (PD) in the three-dimensional structure of the complex between the two proteins (PDB 6M0J [20-21]).  Typically hydrogen bonds in peptides are ≈2.8–3 Å in length between N and O atoms, and an extension to ≈3 or 3.5 Å should lead to rupture. [22].  This same logic was applied to all of the putative hydrogen bond interactions between SAR-CoV 2 RBD and ACE2 PD [21], using a maximum hydrogen bond cutoff length of 3.1 Å.  Distance measurements were made with the RasMol program.  This more stringent procedure resulted in a reduction in the number of putative hydrogen bonded interactions from 12 in Reference 21 to 7 (see below).  In addition, at least one, and possibly two, of the hydrophobic interactions claimed in Reference 21 are questionable, as noted in the table and footnotes below.
Type of interaction  RBD AAs  PD AAs  Distance (Å)  Type of interaction  RBD AAs  PD AAs  Distance (Å) 
Hydrogen bond Q493 K31 2.93 Ionic bond K417 D30 2.91
Y449 D38 2.69 Hydrophobic Y4891 F281 3.39
Q498 Q42 2.93 Y489 L79 6.83
T500 Y41 2.71 Y4892 Y832 3.55
N487 Y83 2.79
G496 K353 3.09
G502 K353 2.79
Notes: 1The hydrophobic interaction between Y489 and F28 is not ideal as the planes of the aromatic rings in the side chains of the two AAs are not parallel, and the closest contact distance is between an oxygen atom of Y498 and the aromatic ring of F28.  2This is most likely not a hydrophobic interaction between the two AAs, as the closest distance between them occurs between the oxygen atoms in both AA side chains

The name-to-peptide method was first described in 2003 [24, 25], and in subsequent years it has been found that among any particular group of names (e.g., Forbes List of the World’s Billionaires) [26] usually about 25% of the names are completely compatible with the IUPAC 1-letter symbolism for the names of AAs.

The first name peptide to be created by chemical synthesis was based on the personal name of a prominent US government official [27]. When laboratory tested, it was found to be capable of inducing migration of human monocytes and neutrophils, and inhibiting the proliferation of human breast cancer (T47D) cells.  Unfortunately, the peptide was not completely compatible with the IUPAC 1-letter symbolism because its design included the letter, O, to represent Ornithine, which had not been assigned by the IUPAC as a 1-letter symbol for the name of an AA.

The second test of the name-to-peptide method involved the selection of a well- known company name, Walmart, and the chemical synthesis and biological testing of the 7 AA peptide, WALMART [28].  The letter composition of the name was completely compatible with the IUPAC one-letter symbolism.  Interestingly, like the first name peptide tested, it was shown to exhibit anticancer activities against breast cancer cells.  The report about peptide WALMART was followed by a report from another research group which described the synthesis and testing of a peptide, HENRYK, based on the personal name of a research group member [29].  This peptide exhibited metal binding properties.

Additional name peptides are currently undergoing testing, but it is now apparent that languages, in conjunction with the IUPAC 1-letter symbols for the names of AAs, represent a very large and novel source of potentially bioactive peptides.

In addition to the potential usefulness of name peptides as biologically active compounds, the name-to-peptide method can serve as a means of educating the public about the concepts of peptides and proteins. Consequently, future name peptide research will concentrate on both organizational (e.g., company) and personal names, as both offer the greatest possibilities of being of interest to the public.

 

Table 5. Results of ClusPro 2.0 [23] docking of peptide SVENSKAAKADEMIEN with the crystal structure of SARS-CoV-2 spike receptor-binding domain (RBD) (modified from PDB 6M0J [20]).  60 models were generated but only 4 had the peptide located at the RBD surface that interacts with ACE2 PD.  In the examples below, the peptide and proteins are shown as ribbon models, and the arrows point to α-helical peptide SVENSKAAKADEMIEN.  The color scheme is yellow for ß-strands, purple for α-helices, blue for turns, and white for unstructured regions.  The average interatomic distance for interacting residues with balanced forces was 2.8 Å (N = 11), and with electrostatic forces was 2.7 Å (N = 12).  Pairs of interacting AA residues are listed as RBD residue/peptide SVENSKAAKADEMIEN residue.
Forces Type  Number of models generated  Models with peptide 

at the interaction interface 

 Interacting 

AA Residues 

 Models with peptide 

at the interaction interface 

 Interacting 

AA Residues 
Balanced 17 Q493/N16

Q498/K6

T500/A7

G496/I14

 Q493/A7&D11

Q498/E15

T500/N16

N487/S1

G496/D11&E15
Electrostatic-

favored

 20 Q493/K9

N487/S1

G496/N16

K417/E12

 Q493/N16

Q498/A10&K6

T500/A7&K6

G496/A10

G502/D11
Hydrophobic-

favored

 13 None
van der Waals + electrostatic 10 None

Table 6.  Results of ClusPro 2.0 [23] docking of peptide SVENSKAAKADEMIEN with the crystal structure of the ACE2 peptidase domain (PD) (modified from PDB 6M0J [20]).  Docking produced 32 models, but none of them had the peptide located at the surface of the ACE2 PD that interacts with SARS-CoV-2 RBD

Forces Type  Number of models generated  Models with peptide at interaction interface 
Balanced 8 0
Electrostatic-favored 8 0
Hydrophobic-favored 4 0
van der Waals

+ electrostatic

 12 0

 

Fig. 2.  Ribbon representations of the peptide backbone conformations of two structural extremes that are commonly seen in the three-dimensional structures of proteins, the ß-strand (top) and the α-helix (bottom).  Peptide SVENSKAAKADEMIEN was modeled with the Deep View/Swiss-PdbViewer program, v.4.1.0. [18] in the two conformations, energy minimized, and the models were saved as PDB files.  The PDB files were then viewed with the RasMol program [19], with the structures displayed as ribbons with monochrome coloration.  Measurements were also done with the RasMol program.  RasMol structures were then transferred to the MS Paint program for the addition of arrows, numbers and letters.  The ß-strand conformation resembles a flattened, slightly twisted, extended ribbon, whereas the α-helix is a compact, coiled, cylindrical structure held in this conformation by hydrogen bonding between amide linkages (i+4>i, where i = AA).

Fig. 3. Stick figure molecular model of peptide SVENSKAAKADEMIEN as a ß-strand.  The model was created from the PDB files described in Fig. 1 and using the RasMol program [19] to generate the stick figure.  Lettering was added with the MS Paint program.  The structure is 49 Å long and has a net charge of -2 at pH 7.

Fig. 4. Electrostatic potential model of peptide SVENSKAAKADEMIEN as a ß-strand.  The model is shown in the same orientation as in Fig. 3.  The model was created from the PDB files described in Fig. 1, and using the Deep View/Swiss-PdbViewer program, v.4.1.0. [18].  Blue color indicates a region of positive charge and red color indicates a region of negative charge.

Fig. 5. Peptide SVENSKAAKADEMIEN as an alpha (α) helix.  This particular peptide structure contains 15 intrachain hydrogen bonds; 12 between amide linkages (i+4>i, where i = AA) and 3 additional hydrogen bonds at the ends of the peptide.  See the Fig. 3 legend for modeling procedures.

Fig. 6.  Electrostatic potential model of peptide SVENSKAAKADEMIEN as an alpha (α) helix.  The model is shown in the same orientation as in Fig. 5.  See the Fig. 4 legend for modeling procedures.  Blue color indicates a region of positive charge and red color indicates a region of negative charge.

Fig. 7.  The three-dimensional structure of the complex of SARS-CoV-2 receptor binding domain (RBD) bound to the ACE2 peptidase domain (PD) (i.e., PDB 6M0J [18]).  The top two figures show the complex in two orientations that differ only in a < 90o rotation about the horizontal axis.  The lower two figures are identical to the upper two figures except that the AAs involved in nonbonding intermolecular interactions (hydrogen bonding, ionic, and hydrophobic; see Table 4) between the two proteins are emphasized as stick figures with CPK coloration.

Declarations

Ethical approval

Not required.

Author contributions

D.W. was the sole author of this article.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

D.W. is a member of Current Bioscience editorial board. This article was reviewed by Current Bioscience editors and reviewers. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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