Trends for isolated amino acids and dipeptides: Conformation, divalent ion binding, and remarkable similarity of binding to calcium and lead

Abstract

We derive structural and binding energy trends for twenty amino acids, their dipeptides, and their interactions with the divalent cations Ca²⁺, Ba²⁺, Sr²⁺, Cd²⁺, Pb²⁺, and Hg²⁺. The underlying data set consists of more than 45,000 first-principles predicted conformers with relative energies up to ~4 eV (~400 kJ/mol). We show that only very few distinct backbone structures of isolated amino acids and their dipeptides emerge as lowest-energy conformers. The isolated amino acids predominantly adopt structures that involve an acidic proton shared between the carboxy and amino function. Dipeptides adopt one of two intramolecular-hydrogen bonded conformations C₅ or . Upon complexation with a divalent cation, the accessible conformational space shrinks and intramolecular hydrogen bonding is prevented due to strong electrostatic interaction of backbone and side chain functional groups with cations. Clear correlations emerge from the binding energies of the six divalent ions with amino acids and dipeptides. Cd²⁺ and Hg²⁺ show the largest binding energies-a potential correlation with their known high acute toxicities. Ca²⁺ and Pb²⁺ reveal almost identical binding energies across the entire series of amino acids and dipeptides. This observation validates past indications that ion-mimicry of calcium and lead should play an important role in a toxicological context.

Figure 1. Molecular systems covered by this study.

Top row: Basic chemical formulae of an amino acid and the corresponding dipeptide. Side chains are represented by R. Lower panel: The chemical structures for the 20 proteinogenic side chains R considered in this work. Where applicable, the alternative side chain protonation states considered in this work are shown as well.

Figure 2

The conformational hierarchies for each amino acids (a) and the capped amino acids (dipeptides) are shown for the isolated (“bare”, red) and, alternatively, for the Ca²⁺ coordinated form (blue). The labels “Ca” and “bare” are accompanied by numbers that reflect the total number of conformers found for each system.

Figure 3. Preferred backbone conformations and protonation states for bare amino acids and for amino acids with Ca²⁺.

(a) Schematic representations of the possible backbone H bonded structure types in amino acids together with a plot detailing the energy hierarchy of types I and II and the zwitterionic state for the isolated amino acids. (b) The two basic backbone-cation conformation types for amino acids with Ca²⁺ and a plot of their relative energies for each amino acid system studied. For clarity, only the lowest energy representatives of the respective structure types are shown. The energy of the respective global minimum is set to 0. The order of the amino acids on the x axis reflects chemical groups in the following sequence: aliphatic, aromatic, basic, acidic, amides, alcohol/thiol, other.

Figure 4

Ramachandran plots for the bare dipeptides (a) and for the dipeptides interacting with Ca²⁺ (b). The ϕ/ψ tuples of the populated conformers of all dipeptides are shown by black crosses. The respective lowest energy conformers for each amino acid type are highlighted by red circles. Structural sketches illustrate the different dominant structure types of the global minima.

Figure 5

Binding affinity of the unprotected amino acids (a) and the dipeptides (b). The building blocks are sorted according to their Ca²⁺ affinity with strongest to weakest affinity from left to right. Open symbols in (a) indicate the zwitterionic form and filled symbols the uncharged/neutral form as the respective global minimum. The amino acids and dipeptides (and their protomers where applicable) were sorted according to the binding energy to Ca²⁺ from the highest to the lowest values.

Figure 6

(a) Binding distances between the divalent cations and their nearest ligands in the lowest-energy conformations of cation-coordinated dipeptide forms of Glu, Arg, GluH, and Cys. The structure images in the insets show the Ca²⁺ coordinated forms and are structurally equivalent for the other cations as well. Different ligand atoms are distinguished by different-colored curves (red: O, blue: N, yellow: S), as noted in the figure. (b) Histograms of cation-O distances for lowest-energy conformers over all dipeptides or uncapped amino acids and the cations covered in the study.