Neighbor effect on conformational spaces of alanine residue in azapeptides

doi:10.1016/j.heliyon.2024.e33159

. 2024 Jun 15;10(12):e33159.

doi: 10.1016/j.heliyon.2024.e33159. eCollection 2024 Jun 30.

Neighbor effect on conformational spaces of alanine residue in azapeptides

Ho-Jin Lee^{1

2}, Shi-Wei Liu³, Máté Sulyok-Eiler^{4

5}, Veronika Harmat^{4

6}, Viktor Farkas^{4

6}, Zoltán Bánóczi^{7

8}, Mouna El Khabchi⁹, Hua-Jun Shawn Fan³, Kimihiko Hirao¹⁰, Jong-Won Song¹¹

Affiliations

¹ Division of Natural and Mathematics Sciences, LeMoyne-Own College, Memphis, TN, 38126, USA.
² Department of Natural Sciences, Southwest Tennessee Community College, Memphis, TN, 38015, USA.
³ College of Chemical Engineering, Sichuan University of Science and Engineering, Zigong City, Sichuan Province, 64300, PR China.
⁴ Laboratory of Structural Biology and Chemistry, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary.
⁵ Hevesy György PhD School of Chemistry, Eötvös Loránd University, Budapest, Hungary.
⁶ HUN-REN - ELTE Protein Modeling Research Group, Budapest, Hungary.
⁷ Department of Organic Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, 1117, Budapest, Hungary.
⁸ HUN-REN-ELTE Research Group of Peptide Chemistry, 1117, Budapest, Hungary.
⁹ LIMAS, Faculty of Sciences Dhar El Mahraz, University Sidi Mohamed Ben Abdallah, Fez, Morocco.
¹⁰ Fukui Institute for Fundamental Chemistry, Kyoto University, Takano, Nishihiraki-cho 34-4, Sakyo-ku, Kyoto, 606-8103, Japan.
¹¹ Department of Chemistry Education, Daegu University, Daegudae-ro 201, Gyeongsan-si, Gyeongsangbuk-do, 38453, Republic of Korea.

PMID: 39021983
PMCID: PMC11253059
DOI: 10.1016/j.heliyon.2024.e33159

Neighbor effect on conformational spaces of alanine residue in azapeptides

Ho-Jin Lee et al. Heliyon. 2024.

. 2024 Jun 15;10(12):e33159.

doi: 10.1016/j.heliyon.2024.e33159. eCollection 2024 Jun 30.

Authors

Affiliations

¹ Division of Natural and Mathematics Sciences, LeMoyne-Own College, Memphis, TN, 38126, USA.
² Department of Natural Sciences, Southwest Tennessee Community College, Memphis, TN, 38015, USA.
³ College of Chemical Engineering, Sichuan University of Science and Engineering, Zigong City, Sichuan Province, 64300, PR China.
⁴ Laboratory of Structural Biology and Chemistry, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary.
⁵ Hevesy György PhD School of Chemistry, Eötvös Loránd University, Budapest, Hungary.
⁶ HUN-REN - ELTE Protein Modeling Research Group, Budapest, Hungary.
⁷ Department of Organic Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, 1117, Budapest, Hungary.
⁸ HUN-REN-ELTE Research Group of Peptide Chemistry, 1117, Budapest, Hungary.
⁹ LIMAS, Faculty of Sciences Dhar El Mahraz, University Sidi Mohamed Ben Abdallah, Fez, Morocco.
¹⁰ Fukui Institute for Fundamental Chemistry, Kyoto University, Takano, Nishihiraki-cho 34-4, Sakyo-ku, Kyoto, 606-8103, Japan.
¹¹ Department of Chemistry Education, Daegu University, Daegudae-ro 201, Gyeongsan-si, Gyeongsangbuk-do, 38453, Republic of Korea.

PMID: 39021983
PMCID: PMC11253059
DOI: 10.1016/j.heliyon.2024.e33159

Abstract

The conformational properties of Alanine (Ala) residue have been investigated to understand protein folding and develop force fields. In this work, we examined the neighbor effect on the conformational spaces of Ala residue using model azapeptides, Ac-Ala-azaGly-NHMe (3, AaG), and Ac-azaGly-Ala-NHMe (4, aGA1). Ramachandran energy maps were generated by scanning (φ, ψ) dihedral angles of the Ala residues in models with the fixed dihedral angles (φ = ±90°, ψ = ±0° or ±180°) of azaGly residue using LCgau-BOP and LCgau-BOP + LRD functionals in the gas and water phases. The integral-equation-formalism polarizable continuum model (IEF-PCM) and a solvation model density (SMD) were employed to mimic the solvation effect. The most favorable conformation of Ala residue in azapeptide models is found as the polyproline II (β_P), inverse γ-turn (γ'), β-sheet (β_S), right-handed helix (α_R), or left-handed helix (α_L) depending on the conformation of neighbor azaGly residue in isolated form. Solvation methods exhibit that the Ala residue favors the β_P, δ_R, and α_R conformations regardless of its position in azapeptides 3 and 4 in water. Azapeptide 5, Ac-azaGly-Ala-NH₂ (aGA2), was synthesized to evaluate the theoretical results. The X-ray structure showed that azaGly residue adopts the polyproline II (β_P) and Ala residue adopts the right-handed helical (α_R) structure in aGA2. The conformational preferences of aGA2 and the dimer structure of aGA2 based on the X-ray structure were examined to assess the performance of DFT functionals. In addition, the local minima of azapeptide 6, Ac-Phe-azaGly-NH₂ (FaG), were compared with the previous experimental results. SMD/LCgau-BOP + LRD methods agreed well with the reported experimental results. The results suggest the importance of weak dispersion interactions, neighbor effect, and solvent influence in the conformational preferences of Ala residue in model azapeptides.

Keywords: And Lcgau-BOP+LRD; Azapeptide; DFT functionals; Foldamer; LCgau-BOP; βI-turn; βII-turn.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Fig. 1**
Chemical structure and dihedral angle nomenclature of Ac-Ala-NHMe (1) and Ac-azaGly-NHMe (2) peptide models, respectively (a, b). Potential energy maps of (c) Ac-Ala-NHMe (1) and (d) Ac-azaGly-NHMe (2), respectively, at the LCgau-BOP + LRD/6-31 + G(d) level in the gas phase. Geometry optimization of all variables except (φ₁, ψ₁) was performed on a grid with 15° spacing. The dihedral angle of ω₀ and ω₁ was set to ∼180°. The energy area from the lowest energy (blue) to 15 kcal/mol (red) is shown. The Ala residue favors β_S(C₅) and γ′ regions; the azaGly residue favors the δ_R and δ_L, β_P, or ε regions. The nomenclature of conformers was adopted from Karplus et al. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 2**
Chemical structures and dihedral angle nomenclature of (a) Ac-Ala-azaGly-NHMe (**3, AaG**) and (b) Ac-azaGly-Ala-NHMe (**4, aGA1**).

**Fig. 3**
Ramachandran energy maps of Ac-Ala(φ₁,ψ₁ = scan)-azaGly (φ₂ = −90°, ψ₂ = 0°)-NHMe (A and B) and Ac-azaGly(φ₁ = −90°, ψ₁ = 0°)-Ala(φ₂,ψ₂ = scan)-NHMe (C, D) at the LCgau-BOP (A and C) and LCgau-BOP + LRD (B and D) with the 6-31 + G(d) basis set. Geometry optimization of all variables except (φ₁, ψ₁) for **AaG** or (φ₂, ψ₂) for **aGA1** was performed on a grid with 15° spacing. The dihedral angle of ω₀ and ω₂ was ∼180°. The energy area from the lowest energy (blue) to 10 kcal/mol (red) is shown. IEF-PCM and SMD solvation methods were used to consider the water environment. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 4**
Ramachandran energy maps of Ac-Ala(φ₁,ψ₁ = scan)-azaGly(φ₂ = +90°, ψ₂ = 0°)-NHMe (A and B) and Ac-azaGly(φ₁ = +90°, ψ₁ = 0°)-Ala(φ,ψ = scan)-NHMe (C and D) at the LCgau-BOP (A and C) and LCgau-BOP + LRD (B and D) with the 6-31 + G(d) basis set. Geometry optimization of all variables except (φ₁, ψ₁) for **AaG** or (φ₂, ψ₂) for **aGA** was performed on a grid with 15° spacing. The dihedral angle of ω₀ and ω₂ was ∼180°. The energy area from the lowest energy (blue) to 10 kcal/mol (red) is shown. IEF-PCM and SMD methods were used to consider the water environment. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 5**
Ramachandran energy maps of Ac-Ala(φ₁,ψ₁ = scan)-azaGly(φ₂ = −90°, ψ₂ = 180°)-NHMe (A and B) and Ac-azaGly(φ₁ = +90°, ψ₁ = 180°)-Ala(φ₂,ψ₂ = scan)-NHMe (C and D) at the LCgau-BOP (A and C) and LCgau-BOP + LRD (B and D) with the 6-31 + G(d) basis set. Geometry optimization of all variables except (φ₁, ψ₁ = scan) for **AaG** or (φ₂, ψ₂ = scan) for **aGA1** was performed on a grid with 15° spacing. The dihedral angle of ω₀ and ω₂ was ∼180°. The energy area from the lowest energy (blue) to 10 kcal/mol (red) is shown. IEF-PCM and SMD solvation methods were used to consider the water effect. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 6**
Ramachandran energy maps of Ac-Ala(φ₁,ψ₁ = scan)-azaGly (φ₂ = +90°, ψ₂ = 180°)-NHMe (A and B) and Ac-azaGly(φ₁ = +90°, ψ₁ = 180°)-Ala(φ₂,ψ₂ = scan)-NHMe (C, D) at the LCgau-BOP (A and C) and LCgau-BOP + LRD (B and D) with the 6-31 + G(d) basis set. Geometry optimization of all variables except (φ₁, ψ₁ = scan) for **AaG** or (φ₂, ψ₂ = scan) for **aGA1** was performed on a grid with 15° spacing. The dihedral angle of ω₀ and ω₂ was set to ∼180°. The energy area from the lowest energy (blue) to 10 kcal/mol (red) is shown. IEF-PCM and SMD solvation methods were used to consider the water effect. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 7**
The most favorable conformation of Ac-Ala-azaGly-NHMe (**3, AaG**) at the SMD/LCgau-BOP + LRD/6–311++G(2d,2p) (A) and population of conformers in the gas and water (B). For y-axis, M1:LCgau-BOP; M2:LCgau + LRD; M3:IEF-PCM/LCgau-BOP; M4:IEF-PCM/LCgau-BOP + LRD; M5: SMD/LCgau-BOP; M6: SMD/LCgau-BOP + LRD; M7: B3LYP; M8:B3LYP-D3; M9: IEF-PCM/B3LYP; **M10**: IEF-PCM/B3LYP-D3; **M11**: SMD/B3LYP; **M12**: SMD/B3LYP-D3 with the 6–311++G(2d,2p) basis set used.

**Fig. 8**
The most favorable conformation of Ac-azaGly-Ala-NHMe (4, **aGA1**) at the SMD/LCgau-BOP + LRD/6–311++G(2d,2p) (A) and population of conformers for azapeptide 4 in the gas and water (B). For y-axis, M1:LCgau-BOP; M2:LCgau + LRD; M3:IEF-PCM/LCgau-BOP; M4:IEF-PCM/LCgau-BOP + LRD; M5: SMD/LCgau-BOP; M6: SMD/LCgau-BOP + LRD; M7: B3LYP; M8:B3LYP-D3; M9: IEF-PCM/B3LYP; **M10**: IEF-PCM/B3LYP-D3; **M11**: SMD/B3LYP; **M12**: SMD/B3LYP-D3 with the 6–311++G(2d,2p) basis set used.

**Fig. 9**
(A) Crystal structure of Ac-azaGly-Ala-NH₂ (azapeptide **5, aGA2**). Atomic displacement ellipsoids are contoured at the 0.5 probability level. Crystal packing with H-bonds is shown as cyan dotted lines: (B) H-bonded chains of molecules along the diagonal of the ab plane of the unit cell (view along the b axis). (C and D) H-bonded 2-D network of molecules in the ab plane(view along unit cell axis a and c, respectively). (E) H-bonded ladder of molecules along unit cell axis b (view along axis a). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 10**
CD spectrum of azapeptide 5. (A) Chemical structure of azapeptide 5 (B) Experimental CD spectrum of azapeptide 5 in water at 5 °C. (C and D) Calculated electronic circular dichroism (ECD) for **aGA2-05** and **aGA2-12** at the SMD/B3LYP-D3 functional with a 6–311++G(2d,2p) basis set in water. NCI analysis of **aGA2-05** and **aGA2-12**. NCI plot shows the regions of attractive (blue) and repulsive (red) interactions, as well as regions of van der Waals interactions (green) for the B3LYP-D3 functional (Multiwfn and VMD software were used to generate the figures). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

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References

1. Perczel A., Angyan J.G., Kajtar M., Viviani W., Rivail J.L., Marcoccia J.F., Csizmadia I.G. Peptide models. 1. Topology of selected peptide conformational potential energy surfaces (glycine and alanine derivatives) J. Am. Chem. Soc. 1991;113(16):6256–6265.
1. Head-Gordon T., Head-Gordon M., Frisch M.J., Brooks C.L., III Pople JA: theoretical study of blocked glycine and alanine peptide analogs. J. Am. Chem. Soc. 1991;113(16):5989–5997.
1. Perczel A., Farkas O., Jákli I., Topol I.A., Csizmadia I.G. Peptide models XXXIII. Extrapolation of low-level Hartree-Fock data of peptide conformation to large basis set SCF, MP2, DFT, and CCSD(T) results. The Ramachandran surface of alanine dipeptide computed at various levels of theory. J. Comput. Chem. 2003;24(9):1026–1042. - PubMed
1. Hudáky I., Hudáky P., Perczel A. Solvation model induced structural changes in peptides. A quantum chemical study on Ramachandran surfaces and conformers of alanine diamide using the polarizable continuum model. J. Comput. Chem. 2004;25(12):1522–1531. - PubMed
1. Wang Z.X., Duan Y. Solvation effects on alanine dipeptide: a MP2/cc-pVTZ//MP2/6-31G** study of (Phi, Psi) energy maps and conformers in the gas phase, ether, and water. J. Comput. Chem. 2004;25(14):1699–1716. - PubMed

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[1] Perczel A., Angyan J.G., Kajtar M., Viviani W., Rivail J.L., Marcoccia J.F., Csizmadia I.G. Peptide models. 1. Topology of selected peptide conformational potential energy surfaces (glycine and alanine derivatives) J. Am. Chem. Soc. 1991;113(16):6256–6265.

[2] Perczel A., Angyan J.G., Kajtar M., Viviani W., Rivail J.L., Marcoccia J.F., Csizmadia I.G. Peptide models. 1. Topology of selected peptide conformational potential energy surfaces (glycine and alanine derivatives) J. Am. Chem. Soc. 1991;113(16):6256–6265.

[3] Head-Gordon T., Head-Gordon M., Frisch M.J., Brooks C.L., III Pople JA: theoretical study of blocked glycine and alanine peptide analogs. J. Am. Chem. Soc. 1991;113(16):5989–5997.

[4] Head-Gordon T., Head-Gordon M., Frisch M.J., Brooks C.L., III Pople JA: theoretical study of blocked glycine and alanine peptide analogs. J. Am. Chem. Soc. 1991;113(16):5989–5997.

[5] Perczel A., Farkas O., Jákli I., Topol I.A., Csizmadia I.G. Peptide models XXXIII. Extrapolation of low-level Hartree-Fock data of peptide conformation to large basis set SCF, MP2, DFT, and CCSD(T) results. The Ramachandran surface of alanine dipeptide computed at various levels of theory. J. Comput. Chem. 2003;24(9):1026–1042. - PubMed

[6] Perczel A., Farkas O., Jákli I., Topol I.A., Csizmadia I.G. Peptide models XXXIII. Extrapolation of low-level Hartree-Fock data of peptide conformation to large basis set SCF, MP2, DFT, and CCSD(T) results. The Ramachandran surface of alanine dipeptide computed at various levels of theory. J. Comput. Chem. 2003;24(9):1026–1042. - PubMed

[7] Hudáky I., Hudáky P., Perczel A. Solvation model induced structural changes in peptides. A quantum chemical study on Ramachandran surfaces and conformers of alanine diamide using the polarizable continuum model. J. Comput. Chem. 2004;25(12):1522–1531. - PubMed

[8] Hudáky I., Hudáky P., Perczel A. Solvation model induced structural changes in peptides. A quantum chemical study on Ramachandran surfaces and conformers of alanine diamide using the polarizable continuum model. J. Comput. Chem. 2004;25(12):1522–1531. - PubMed

[9] Wang Z.X., Duan Y. Solvation effects on alanine dipeptide: a MP2/cc-pVTZ//MP2/6-31G** study of (Phi, Psi) energy maps and conformers in the gas phase, ether, and water. J. Comput. Chem. 2004;25(14):1699–1716. - PubMed

[10] Wang Z.X., Duan Y. Solvation effects on alanine dipeptide: a MP2/cc-pVTZ//MP2/6-31G** study of (Phi, Psi) energy maps and conformers in the gas phase, ether, and water. J. Comput. Chem. 2004;25(14):1699–1716. - PubMed

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Neighbor effect on conformational spaces of alanine residue in azapeptides

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Neighbor effect on conformational spaces of alanine residue in azapeptides

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Affiliations

Abstract

Conflict of interest statement

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Abstract

Conflict of interest statement

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