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. 2023 Jul 25;24(15):11877.
doi: 10.3390/ijms241511877.

Elucidating the Racemization Mechanism of Aliphatic and Aromatic Amino Acids by In Silico Tools

Mateo S Andino  1 , José R Mora  1 , José L Paz  2 , Edgar A Márquez  3 , Yunierkis Perez-Castillo  4 , Guillermin Agüero-Chapin  5   6
Affiliations

Elucidating the Racemization Mechanism of Aliphatic and Aromatic Amino Acids by In Silico Tools

Mateo S Andino et al. Int J Mol Sci. .

Abstract

The racemization of biomolecules in the active site can reduce the biological activity of drugs, and the mechanism involved in this process is still not fully comprehended. The present study investigates the impact of aromaticity on racemization using advanced theoretical techniques based on density functional theory. Calculations were performed at the ωb97xd/6-311++g(d,p) level of theory. A compelling explanation for the observed aromatic stabilization via resonance is put forward, involving a carbanion intermediate. The analysis, employing Hammett's parameters, convincingly supports the presence of a negative charge within the transition state of aromatic compounds. Moreover, the combined utilization of natural bond orbital (NBO) analysis and intrinsic reaction coordinate (IRC) calculations confirms the pronounced stabilization of electron distribution within the carbanion intermediate. To enhance our understanding of the racemization process, a thorough examination of the evolution of NBO charges and Wiberg bond indices (WBIs) at all points along the IRC profile is performed. This approach offers valuable insights into the synchronicity parameters governing the racemization reactions.

Keywords: amino acids; density functional theory; intrinsic reaction coordinates; natural bond orbital; racemization.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Theoretical activation energies vs. experimental activation energies of racemization of aromatic and aliphatic amino acids.
Figure 2
Figure 2
Hammett σ plot using ΔG for calculations.
Figure 3
Figure 3
Hammett σ plot using ΔH for calculations.
Figure 4
Figure 4
IRC energy profiles for racemization of aromatic compounds.
Figure 5
Figure 5
IRC energy profiles for racemization of aliphatic compounds.
Figure 6
Figure 6
IRC electronic flux profile for racemization of aromatic compounds.
Figure 7
Figure 7
IRC electronic flux profile for racemization of aliphatic compounds.
Figure 8
Figure 8
IRC reaction force profile for racemization of aromatic compounds.
Figure 9
Figure 9
IRC reaction force profile for racemization of aliphatic compounds.
Figure 10
Figure 10
Bond length difference from reactant to product. H5-O6 formation length diminishes and C1-H5 cleavage length increases.
Figure 11
Figure 11
IRC C1-H5-O6 bond angle profile for racemization of aliphatic compounds.
Figure 12
Figure 12
IRC N3-C1-C2-C4 dihedral angle profile for racemization of aromatic compounds.
Figure 13
Figure 13
IRC N3-C1-C2-C4 dihedral angle profile for racemization of aliphatic compounds.
Figure 14
Figure 14
C1 NBO charge profile for racemization of aromatic compounds.
Figure 15
Figure 15
C1 NBO charge profile for racemization of aliphatic compounds.
Figure 16
Figure 16
Wiberg bond index comparison between the C1-H5 bond and H5-O6 across IRC calculations.
Scheme 1
Scheme 1
Racemization mechanism with a carbanion intermediate.
Scheme 2
Scheme 2
N3-C2-C1 (red) and C2-C1-C4 (blue) planes considered in dihedral angle calculations.
See this image and copyright information in PMC

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