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Probably a basic question, but are all possible dipeptides synthesizable? For 20 amino acids, there should be in principle 190 dipeptides; do they all exist or is there chemistry that makes some combinations unstable? A straight forward generalization would be to ask what percentage of peptides (or proteins) are synthesizable (in the lab or in cells).

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    $\begingroup$ I'm pretty sure any peptide can be synthesized in a lab. Length is probably limited by yield, but I imagine that can be overcome by, say, ligating or elongating previously synthesized peptides. $\endgroup$ – canadianer Sep 3 '15 at 17:25
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    $\begingroup$ @secretlyfamous You mention cells in your question, which is why I brought them up. In cells, N can be quite large, well over 34,000 in the case of the muscle protein titin. As I mentioned in my previous comment, there is a large body of literature on the capabilities and limitations of chemical polypeptide synthesis, with yield inversely proportional to length. A quick Google search yielded this page, which describes the synthesis of 169 AA by the ligation of several shorter precursors. $\endgroup$ – MattDMo Sep 3 '15 at 19:17
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    $\begingroup$ @canadianer I highly doubt titin could be synthesized in the lab, though with a good deal of work a lot of (much) smaller proteins probably could. N is not infinite, though. I know antibodies can't be chemically synthesized (two 50 kDa chains and two 25 kDa ones for IgG). Plus, post-translational modifications like disulfide bonds could present a lot of problems. $\endgroup$ – MattDMo Sep 3 '15 at 19:21
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    $\begingroup$ @MattDMo I really don't know anything about it, though I did say peptide and not protein. Is it impossible to synthesize antibodies or just not practical? $\endgroup$ – canadianer Sep 3 '15 at 20:22
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    $\begingroup$ Yes. There is nothing magical or mysterious about a peptide bond. $\endgroup$ – mdperry Sep 4 '15 at 5:44
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I see no reason why not. Just to make sure, I decided to test. I ran a search on all human proteins (using the UniProt flat file) for all possible dipeptide combinations of the 20 standard amino acids (selenocysteine is also present in humans but only in 22--or so, depending on how you count them--proteins, so I wouldn't expect all possible sec-containing dipeptides to be present) .

As expected, each of the 400 possible dipeptides were indeed present in at least one human protein. In case anyone wants to repeat this, the "protocol" is as follows:

  1. Download the human flat file from Expassy.
  2. Extract the peptide sequences

    perl -ne 'if(s/^\s+//){s/\s+//g;print}' human.flat > human.pep
    
  3. Generate the list of possible dipeptides:

    AA
    AC
    AD
    AE
    AF
    AG
    AH
    AI
    AK
    AL
    AM
    AN
    AP
    AQ
    AR
    AS
    AT
    AV
    AW
    AY
    CA
    CC
    CD
    CE
    CF
    CG
    CH
    CI
    CK
    CL
    CM
    CN
    CP
    CQ
    CR
    CS
    CT
    CV
    CW
    CY
    DA
    DC
    DD
    DE
    DF
    DG
    DH
    DI
    DK
    DL
    DM
    DN
    DP
    DQ
    DR
    DS
    DT
    DV
    DW
    DY
    EA
    EC
    ED
    EE
    EF
    EG
    EH
    EI
    EK
    EL
    EM
    EN
    EP
    EQ
    ER
    ES
    ET
    EV
    EW
    EY
    FA
    FC
    FD
    FE
    FF
    FG
    FH
    FI
    FK
    FL
    FM
    FN
    FP
    FQ
    FR
    FS
    FT
    FV
    FW
    FY
    GA
    GC
    GD
    GE
    GF
    GG
    GH
    GI
    GK
    GL
    GM
    GN
    GP
    GQ
    GR
    GS
    GT
    GV
    GW
    GY
    HA
    HC
    HD
    HE
    HF
    HG
    HH
    HI
    HK
    HL
    HM
    HN
    HP
    HQ
    HR
    HS
    HT
    HV
    HW
    HY
    IA
    IC
    ID
    IE
    IF
    IG
    IH
    II
    IK
    IL
    IM
    IN
    IP
    IQ
    IR
    IS
    IT
    IV
    IW
    IY
    KA
    KC
    KD
    KE
    KF
    KG
    KH
    KI
    KK
    KL
    KM
    KN
    KP
    KQ
    KR
    KS
    KT
    KV
    KW
    KY
    LA
    LC
    LD
    LE
    LF
    LG
    LH
    LI
    LK
    LL
    LM
    LN
    LP
    LQ
    LR
    LS
    LT
    LV
    LW
    LY
    MA
    MC
    MD
    ME
    MF
    MG
    MH
    MI
    MK
    ML
    MM
    MN
    MP
    MQ
    MR
    MS
    MT
    MV
    MW
    MY
    NA
    NC
    ND
    NE
    NF
    NG
    NH
    NI
    NK
    NL
    NM
    NN
    NP
    NQ
    NR
    NS
    NT
    NV
    NW
    NY
    PA
    PC
    PD
    PE
    PF
    PG
    PH
    PI
    PK
    PL
    PM
    PN
    PP
    PQ
    PR
    PS
    PT
    PV
    PW
    PY
    QA
    QC
    QD
    QE
    QF
    QG
    QH
    QI
    QK
    QL
    QM
    QN
    QP
    QQ
    QR
    QS
    QT
    QV
    QW
    QY
    RA
    RC
    RD
    RE
    RF
    RG
    RH
    RI
    RK
    RL
    RM
    RN
    RP
    RQ
    RR
    RS
    RT
    RV
    RW
    RY
    SA
    SC
    SD
    SE
    SF
    SG
    SH
    SI
    SK
    SL
    SM
    SN
    SP
    SQ
    SR
    SS
    ST
    SV
    SW
    SY
    TA
    TC
    TD
    TE
    TF
    TG
    TH
    TI
    TK
    TL
    TM
    TN
    TP
    TQ
    TR
    TS
    TT
    TV
    TW
    TY
    VA
    VC
    VD
    VE
    VF
    VG
    VH
    VI
    VK
    VL
    VM
    VN
    VP
    VQ
    VR
    VS
    VT
    VV
    VW
    VY
    WA
    WC
    WD
    WE
    WF
    WG
    WH
    WI
    WK
    WL
    WM
    WN
    WP
    WQ
    WR
    WS
    WT
    WV
    WW
    WY
    YA
    YC
    YD
    YE
    YF
    YG
    YH
    YI
    YK
    YL
    YM
    YN
    YP
    YQ
    YR
    YS
    YT
    YV
    YW
    YY
    

    Save that list as dip.txt.

  4. Use that file to search the protein sequences:

    perl -ne 'BEGIN{open(A,"human.pep"); while(<A>){chomp; $k.=$_}}; chomp; print "$_\n" if $k=~/$_/  ' dip.txt
    

The script above will print each dipeptide that was found in at least one protein. Since all were printed, all dipeptides exist in the human proteome.

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  • $\begingroup$ thanks for the detailed answer. Your answer looks at things from a slightly different angle (dipeptide occurrence in proteins) which is actually a more interesting angle. I asked a simplified question about dipeptide occurrence on their own first; the answer to that seems to be yes. I am also in fact interested in the case for larger N and the statistics of their occurrence in proteins. I'll take a shot at modifying your script to do some more searches. BTW, you caught a mistake in the number of possible combinations of dipeptides, it is in fact 400 and not 190 as I put in the question. $\endgroup$ – unknown Sep 4 '15 at 20:53
  • $\begingroup$ Yeah, a negative result wouldn't have been conclusive but a positive one is. My assumption was that if a dipeptide occurs in a protein, it can be synthesized. You seem to be suggesting that the dipeptide alone might not be stable and could need the rest of the peptide in order to be so. That's quite interesting and may well be the case but my structural chemistry knowledge is pitiful so I won't venture an opinion on it. As for larger Ns, my script won't help you much. It's a very simplistic approach. $\endgroup$ – terdon Sep 4 '15 at 21:35

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