Conformational analysis of the sea anemone and sea pansies
neuropeptide Antho-RFamide (Glu
1-Gly
2-Arg
3-Phe
4-NH
2)
by molecular-mechanics calculations (*)
L. DEMI.R(1), N. SEFTEROG˘ LU(2), G. BUDAK(1), A. KARABULUT(1) and Y. S¸AHI.N(1)
(1) Atatürk University, Faculty of Arts and Sciences, Department of Physics
25240 Erzurum, Türkiye
(2) Bakü State University, Faculty of Physics - Azerbaycan (ricevuto il 3 Luglio 1995; approvato il 19 Febbraio 1997)
Summary. — Conformation energy-minimization for the sea anemone neuropeptide Antho-RFamide (Glu1-Gly2-Arg3-Phe4-NH
2) was computed by molecular mechanics (MM) using an initial investigation of staggered forms examining the linkage bonds characterized by the torsion angles f, c and v and the Antho-RFamide side groups characterized by the torsion angles x1, x2, x3Rsubsequently. The energy-map for each monopeptide of the Antho-RFamide was drawn in the range between 21807 and 1807 by the step 207. Conformation facilities for monopeptides were decided from these maps. Conformation facilities for monopeptides were examined from the best choice and the results were used in the examination of dipeptides. (Glu1-Gly2) and ( Arg3-Phe4-NH
2) dipeptides of the (Glu1-Gly2-Arg3-Phe4-NH2) neuropeptide were examined separately. The most convenient alternation of these was determined and used in the conformation analysis of the whole molecule.
PACS 87.15.He – Molecular dynamics and conformational changes.
1. – Introduction
The neuropeptide Antho-RFamide (Glu1-Gly2-Arg3-Phe4-NH
2) was isolated from sea
anemones and sea pansies by Grimmelikhuijzen, Rinehart and Spencer [1]. The conformational state of each residue in neuropeptide is classified by short, medium and long range.
On the theoretical side, ab initio orbital calculations and molecular-mechanics calculations have been employed to study the conformational structures and the related energy states of the various molecules [2-10]. Andrew et al. [11] computed the conformational energies for models of the disaccharide b-D-fructofuranosyl-( 2 K6)-b-D-glucopyranoside by molecular mechanics. To investigate the local
(*) The authors of this paper have agreed to not receive the proofs for correction.
interactions in tripeptide sequences composed of amino acids having aromatic side chains, Oka et al. [12] theoretically carried out the conformational analysis of N-acetyl-N8-methylamide of the Phe-Phe-Phe tripeptide using conformational energy-minimization procedure. Subramanian et al. [13] determined the crystal structure of the dipeptide tert (C10H18N2O5; H2O).
We have modeled the isolated molecule to obtain information about the energetically most likely conformations of this neuropeptide Antho-RFamide by computing its steric energies at different torsion angles of the central linkage bonds, namely, the f, c and v angles, as well as at the staggered angles of the side groups. 2. – Theoretical
Conformational energy calculations of the (Glu1-Gly2-Arg3-Phe4-NH
2) tetrapeptide
were carried out with an Empirical Conformational Energy Program for Peptides (ECEPP) [14]. The main point of the model concerns the consistency of all types of intra- and inter-molecular interactions in the stable low-energy structures of peptides and proteins. During minimization all the backbone f, c and v and side chain
x1, x2, x3R dihedral angles were allowed to vary. All best combinations of
single-residues were used as starting conformations.
The details of conformational procedure as well as energy functions and semi-empirical parameters used to evaluate nonbonded and electrostatic interactions, hydrogen bonding and torsional component, have already been described by using a semi-empirical method [15]. The hydrogen bond length and the bond energy are found out in the present conformation analysis as follows:
Atomic groups in H bond Bond length Energy (kcal/mol)
NH( Glu1), OE2( Glu1) OE2( Glu1), NH( Arg3) NH( Phe4), CO( Phe4) CO( Phe4), NH 2 2.31 1.99 2.23 2.52 20 .58 21 .22 20 .70 20 .33
TABLE I. – Distribution of conformations of the (Glu1-Gly2-Arg3-Phe4-NH
2) due to the relative
energies.
Shape Energy interval (kcal Q mol21)
0–1 1–2 2–3 3–4 4–5 5–10 D 10 f f f 2 2 6 12 7 63 32 f f e 2 1 6 18 38 89 25 f e f 1 1 8 3 4 81 11 e f f — — — — 1 59 19 e f e — — — 2 2 80 24 e e f — — 2 — 2 49 39 f e e — — — 6 4 20 8 e e e — — — — 4 84 47
TABLE II. – Energy parameters of the low-energy conformations of the
( Glu1-Gly2-Arg3-Phe4-NH
2) tetrapeptides (kcalQmol21).
Form Enb Eel Etors Erel
B322PR3233333B12 216 .30 21 .73 3.89 0.31 B322PB1333333B32 215 .21 22 .22 2.98 0.00 B322LR3331333B12 214 .12 21 .66 2.31 0.98 R332PR3333133B22 212 .93 20 .94 3.29 3.86 R332PR2333333L32 212 .08 20 .77 3.05 4.64 R332LR3333133B22 214 .08 20 .03 5.01 3.35 B332LB3333333B12 211 .23 22 .22 2.10 3.10 L322BB3333332B12 211 .53 21 .62 3.23 4.53
TABLEIII. – The intra- and inter-residue interaction energies (kcalQmol21) in the conformation (ffe) with Erel4 0 .00 kcalQmol21of the neuropeptide Antho-RFamide ( Glu1Gly2Arg3Phe4NH2).
Glu1 Gly2 Arg3 Phe4NH
2 Glu1 2 0 .69 2 0 .84 2 2 .84 2 1 .9 Gly2 — 1.18 2 0 .62 2 1 .92 Arg3 — — 2 4 .17 2 2 .98 Phe4NH 2 — — — 2 2 .65
TABLE IV. – The intra- and inter-residue interaction energies (kcalQmol21) in the conformation (fff ) with Erel4 0 .31 kcalQmol21of the neuropeptide Antho-RFamide ( Glu1Gly2Arg3Phe4NH2).
Glu1 Gly2 Arg3 Phe4NH
2 Glu1 2 0.73 2 1.49 2 2.24 2 5.26 Gly2 — 1.22 2 1.17 2 1.62 Arg3 — — 2 3.35 2 3.18 Phe4NH 2 — — — 2 0.22
TABLE V. – The intra- and inter-residue interaction energies (kcalQmol21) in the conformation (eff) with Erel4 0 .31 kcalQmol21of the neuropeptide Antho-RFamide ( Glu1Gly2Arg3Phe4NH2).
Glu1 Gly2 Arg3 Phe4NH
2 Glu1 2 0.74 0.64 2 1.85 2 3.22 Gly2 — 1.28 2 0.95 2 0.52 Arg3 — — 2 3.84 2 3.70 Phe4NH 2 — — — 2 2.88
TABLEVI. – Numerical values of dihedral angles of rotation about the backbond side chain bonds
in lowest-enegy structures of the neuropeptide Antho-RFamide.
f1 x11 x12 x13 c1 v1 f2 c2 277.99 2175.170 63.75 2103.24 2142.27 166.48 102.63 277.69 v2 f3 x21 x22 x23 x24 x25 x26 178.48 2104.76 2177.05 178.38 179.61 179.93 179.81 179.77 x27 c3 v3 f4 x31 x32 c4 v4 179.75 127.57 2175.46 2163.05 54.84 287.110 164.32 179.51
From each shape of these energy functions, the 8 lowest energy forms were extracted (table I). Table II lists the lowest 8 energies (Erel) of possible 864 structural
variants for the Antho-RFamide. These structures exhibit 65 backbone forms belonging to 8 shapes, possible in principle for a tetrapeptide. These also exhibit a considerable range of energies. In addition, the calculated values of the elements of the triangular matrices of energy components for the three most preferable structures of Antho-RFamide are given in table III, IV and V. These matrices provide a good illustration for all inter- and intra-residue interaction, as well as for an efficiency and energy distribution of the contacts. Numerical values of dihedral angles of rotation about the backbond and side chain bonds in lowest-energy structures of Antho-RFamide are given in table VI. The coordinates of the lowest-energy conforma-tion are listed in table VII.
3. – Result and discussion
The structure of neuropeptide Antho-RFamide (Glu1-Gly2-Arg3-Phe4-NH 2) is
investigated by the semi-empirical conformational analysis method, in detail. The values of the geometry and energy parameters of the stabilized states available in the polarized environment are found out and then the best form of the relevant interaction energies is calculated (table I, II).
Neuropeptide Antho-RFamide (Glu1-Gly2-Arg3-Phe4-NH
2) consists of the amino acid
residues, which have different physical and chemical properties. The first and third amino acid residues (Glu1 and Arg3) of the molecule have total electrical charges and
movable side chains. The electrostatic interaction due to the total electrical charges of each side chain of Glu1and Arg3, oppositely charged in sign, affects the stability of the
conformational structure of the molecule. Amino acid Gly2 takes place between these two amino acid residues and provides possibilities for the contact between the two residues since it has a movable backbone because of the inexistence of the side chain. NH2 and amino acid Glu1 are also electrically positively charged. This weakens the
interactions between the side chains of Arg3 and Glu1 since Glu1 interacts with both
TABLE VII. – Coordinates of the lowest energy conformation of neuropeptide Antho-RFamide ( Glu1Gly2Arg3Phe4NH
2). Number Atom x y z 1 H 0.0000 0.0000 0.0000 2 N 0.0000 1.0000 0.0000 3 H 20 .4713 1.3338 0.8164 4 CA 1.2429 1.7468 0.0000 5 HA 1.8873 1.3701 20 .6654 6 CB 1.0281 3.1688 20 .5221 7 HB 0.5352 3.1368 21 .4938 8 HB 0.3511 3.7088 0.1399 9 CG 2.3573 3.9182 20 .6347 10 HG 2.1755 4.9566 20 .9117 11 HG 2.8494 3.9489 0.3374 12 CD 3.2748 3.2556 21 .6643 13 OE1 3.1066 3.3949 22 .8646 14 OE2 4.2183 2.5562 21 .3342 15 C 1.8517 1.7643 1.4036 16 O 1.1307 1.8583 2.3956 17 N 3.1679 1.6724 1.4419 18 H 2.5894 1.9413 2.2120 19 CA 4.5240 1.2998 1.7949 20 HA 4.5178 0.7674 2.6414 21 HA 4.9544 0.8263 1.0264 22 C 5.3787 2.5384 2.0712 23 O 5.6353 2.8749 3.2261 24 N 5.7944 3.1806 0.9954 25 H 5.5995 2.8880 0.0593 26 CA 6.5857 4.3905 1.1071 27 HA 6.9675 4.4854 2.0265 28 CB 7.7840 4.3516 0.1566 29 HB 8.4158 3.4965 0.3966 30 HB 7.4344 4.3607 20 .8758 31 CG 8.6591 5.5951 0.3264 32 HG 8.1027 6.4807 0.0194 33 HG 9.0332 5.6487 1.3487 34 CD 9.8915 5.5258 20 .5776 35 HD 9.5798 5.4806 21 .6211 36 HD 10.5017 4.6657 20 .3017 37 NE 10.7165 6.7421 20 .4029 38 HE 10.3971 7.4331 0.2456 39 CQ 11.8618 6.9714 21 .0596 40 NZ1 12.3251 6.0680 21 .9341 41 HZ1 13.1780 6.2407 22 .4268 42 HZ1 11.8180 5.2211 22 .0940 43 NZ2 12.5437 8.1042 20 .8419 44 HZ2 13.4003 8.2737 21 .3292 45 HZ2 12.1959 8.7801 20 .1921 46 C 5.7262 5.6153 0.7876 47 O 5.0774 5.6675 20 .2561
TABLEVII (Continued). Number Atom x y z 48 N 5.7494 6.5670 1.7020 49 H 6.3293 6.5460 2.5164 50 CA 4.9079 7.7414 1.5790 51 HA 4.8884 8.0502 0.6281 52 CB 3.4563 7.3811 1.9013 53 HB 2.8391 8.2782 1.8519 54 HB 3.0649 6.7209 1.1273 55 CG 3.2945 6.7200 3.2716 56 CD1 3.4343 5.3731 3.3976 57 HD1 3.6617 4.7646 2.5223 58 CE1 3.2841 4.7596 4.6694 59 HE1 3.3963 3.6801 4.7704 60 CQ 3.0004 5.5189 5.7614 61 HQ 2.8851 5.0480 6.7376 62 CE2 2.8605 6.8658 5.6354 63 HE2 2.6331 7.4744 6.5106 64 CD2 3.0107 7.4793 4.3636 65 HD2 2.8986 8.5588 4.2626 66 C 5.4162 8.8486 2.5046 67 O 6.2092 8.5912 3.4090 68 N 4.9406 10.0528 2.2474 69 H 5.2178 10.8308 2.8113 70 H 4.3032 10.1871 1.4888
group in its side chain. These make the Van der Waals (nonvalent) interactions more important to stabilize molecule than the electrostatic and torsion interactions (table II). Conformational structure of the molecule is weakly dependent on external effects because the contribution of the hydrogen bond energy to the stabilization is relatively small. Consequently, it is possible that the molecule keeps the biological properties and activities in the media with various physical and chemical properties.
Folded and partially folded (fff, ffe, fef, eff) form of the molecule (Glu1-Gly2-Arg3-Phe4-NH
2) is more favorable in the distribution of the relative energy of
the conformational structure (table I). In spite of the various geometry of the structures corresponding to these forms, similarity of the energy parameters may indicate 1) the functionality and 2) the big possibility of binding with receptor of the molecule.
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