Non-enzymatic glycation of proteins has been implicated as an important cause of the complications associated with diabetes and Alzheimer disease. It is well known that glycation involves the reactivity of, primarily, the ε-amino group of the lysines present in the protein. The immediate chemical environment of an amino group modulates the glycation reaction. In this work, several model helical peptides for protein glycation has been studied by resorting to QM:MM calculations through the ONIOM methodology. Some Conceptual DFT descriptors have been calculated that allowed the comparison of the chemical reactivity between the different model peptides in terms of the position of the Lys group and other spatially proximate amino acid residues.
The nonenzymatic reaction between reducing carbohydrates and the amino groups of amino acids, peptide and proteins is called glycation and through a series of chain reaction leads to the formation of Advanced Glycation End- products (AGEs). These molecules have been related to some diseases like diabetes, Alzheimer and Parkinson. Nonenzymatic glycation of proteins has been implicated as an important cause of the complications associated with diabetes and Alzheimer disease. It is well known that glycation involves the reactivity of, primarily, the ε-amino group of the lysines present in the protein.
The immediate chemical environment of an amino group modulates the glycation reaction. Some years ago, Venkatraman et al [
Therefore, we consider that it will be of practical interest to develop a the- oretical and computational tool that could be an aid for the prediction of the preferred glycation sites for the different possible conformational structures of model peptides because they could be an aid in the development of AGE in- hibitors.
Thus, the objective of this work is to predict the preferred glycation sites of the model helical peptides proposed by Venkatraman et al [
As this work is part of an ongoing project, the theoretical background is analog to that presented in previous research [
Following the lines of our previous work [
The energies of the neutral, positive and negative peptides were obtained within the framework of QM:MM calculations performed through the ONIOM method [
The following peptides proposed by Venkatraman et al [
KD4: Ac-EYUALKAUADUAAUR-NH2
KD2: Ac-EYUALUAKADUAAUR-NH2
KH4: Ac-EYUALKAUAHUAAUR-NH2
RKD4: Ac-EYRULKAUADUAAUA-NH2
K14: Ac-EYUALKAUAUAAUR-NH2
From the cluster analysis, some members were selected for further analysis: 3 for KD4, 4 for KD2, 3 for KH4, 3 for RKD4 and 1 for K14.
The ionization potentials
Within Conceptual DFT, the Fukui function is defined in terms of the derivative of
By applying a finite difference approximation to the previous expression, two definitions of Fukui functions depending on total electronic densities are obtained:
Morell et al. [
Peptide | ( | ( | ||||||
---|---|---|---|---|---|---|---|---|
KD4-1 | 6.241 | 0.336 | 3.289 | 5.905 | 0.916 | 3.845 | 0.556 | 4.402 |
KD4-2 | 6.323 | 0.399 | 3.361 | 5.924 | 0.954 | 3.958 | 0.597 | 4.555 |
KD4-3 | 6.451 | 0.350 | 3.400 | 6.101 | 0.947 | 3.976 | 0.576 | 4.552 |
KD2-1 | 6.418 | 0.382 | 3.400 | 6.036 | 0.958 | 3.992 | 0.592 | 4.585 |
KD2-2 | 6.297 | 0.216 | 3.257 | 6.081 | 0.872 | 3.753 | 0.496 | 4.249 |
KD2-3 | 6.297 | 0.216 | 3.257 | 6.081 | 0.872 | 3.753 | 0.496 | 4.249 |
KD2-4 | 6.306 | 0.172 | 3.239 | 6.133 | 0.855 | 3.714 | 0.474 | 4.188 |
KH4-1 | 6.447 | 0.340 | 3.394 | 6.106 | 0.943 | 3.964 | 0.571 | 4.535 |
KH4-2 | 6.329 | 0.382 | 3.355 | 5.946 | 0.947 | 3.943 | 0.587 | 4.530 |
KH4-3 | 6.371 | 0.275 | 3.323 | 6.096 | 0.906 | 3.854 | 0.531 | 4.385 |
RKD4-1 | 6.228 | 0.578 | 3.403 | 5.649 | 1.025 | 4.104 | 0.701 | 4.806 |
RKD4-2 | 6.407 | 0.308 | 3.357 | 6.099 | 0.924 | 3.908 | 0.551 | 4.459 |
RKD4-3 | 6.358 | 0.350 | 3.354 | 6.008 | 0.936 | 3.925 | 0.571 | 4.496 |
K14-1 | 6.377 | 0.234 | 3.306 | 6.143 | 0.889 | 3.816 | 0.510 | 4.326 |
nucleophilic attack on atom k and then that atom acts as an electrophilic 100 species; conversely, when
In 2014, Domingo proposed the Parr functions
The condensed Fukui functions
The first thing that can be observed from
However, it can be observed from
Peptide | MPA | HPA | ||||
---|---|---|---|---|---|---|
KD4-1 | 0.417 | −0.424 | 0.537 | 0.411 | −0.537 | 0.514 |
KD4-2 | 0.728 | −0.732 | 0.834 | 0.656 | −0.834 | 0.803 |
KD4-3 | 0.766 | −0.771 | 0.860 | 0.678 | −0.860 | 0.832 |
KD2-1 | 0.753 | −0.759 | 0.842 | 0.665 | −0.842 | 0.812 |
KD2-2 | 0.689 | −0.690 | 0.810 | 0.615 | −0.810 | 0.774 |
KD2-3 | 0.689 | −0.690 | 0.810 | 0.615 | −0.810 | 0.774 |
KD2-4 | 0.554 | −0.564 | 0.618 | 0.508 | −0.618 | 0.603 |
KH4-1 | 0.765 | −0.770 | 0.858 | 0.677 | −0.858 | 0.830 |
KH4-2 | 0.737 | −0.740 | 0.844 | 0.662 | −0.844 | 0.813 |
KH4-3 | 0.320 | −0.324 | 0.404 | 0.322 | −0.404 | 0.385 |
RKD4-1 | 0.582 | −0.596 | 0.707 | 0.524 | −0.707 | 0.683 |
RKD4-2 | 0.751 | −0.753 | 0.859 | 0.669 | −0.859 | 0.826 |
RKD4-3 | 0.724 | −0.729 | 0.835 | 0.636 | −0.835 | 0.794 |
R14-1 | 0.319 | −0.326 | 0.400 | 0.318 | −0.400 | 0.383 |
different for the different conformational structures of the model peptides. The amino groups of the Lys residues in the model helical peptides make these systems to behave as electrodonating molecules in the glycation reaction. Thus, KD4-3 and KD4-2 will be more reactive than KD4-1. The same trend is observed for the chemical hardness
Indeed, the sites for glycation will be also the preferred sites for protonation. Thus, the pKa’s of the Lys residues will be also dependent on the conformational structures of the model peptides. Moreover, the trend in the pKa of the different conformers may be predicted in terms of the local hypersoftness (LHS), which is a local reactivity descriptor that has been defined so that it permits to measure local reactivitiesaccording to the molecular size [
The preferred glycation sites of several model helical peptides have been established by resorting to the calculation of some Conceptual DFT descriptors like the Fukui function indexes, the condensed dual descriptor
This work has been partially supported by CIMAV, SC and Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) through Grant 219566/2014 for Basic Science Research and Grant 265217/2016 for a Foreign Sabbatical Leave. Daniel Glossman-Mitnik conductedthis work while a Sabbatical Fellow at the University of the Balearic Islands from which support is gratefully acknowledged. This work was cofunded by the Ministerio de Economía y Competitividad (MINECO) and the European Fund for Regional Development (FEDER) 175 (CTQ2014-55835-R).
Frau, J. and Gloss- man-Mitnik, D. (2017) Comparative Study of the Chemical Reactivity of Helical Peptide Models for Protein Glycation. Computational Chemistry, 5, 65-73. https://doi.org/10.4236/cc.2017.52006