Effect of minor differences in sequences of huntingtin peptides on their interactions with sucrose and trehalose: in silico investigation

Abstract

In this work the behavior of two Huntingtin (Htt) peptides in mixtures with water and either sucrose or trehalose were investigated by classical molecular dynamics (MD) simulations. Structures of those peptides are listed in the Protein Databank as 2LD2 (Biophys. J., 2013, 105, 699-710) and 6N8C (Proc. Natl. Acad. Sci., 2019, 116, 9, 3562-3571). The principal difference between those peptides is in their C- and N-terminals. Since Huntington’s disease is related to the aggregation of proteins containing consecutive polyglutamine in their amino acid chains, the aim was to investigate if smaller amounts of disaccharides could reduce aggregation of two peptides from the Htt protein. Computational results revealed that both sugars alter the secondary structures of peptides and decrease the total number of contacts (the sum of hydrophobic contacts and hydrogen bonds) between these biomolecules. However, regarding only the number of hydrogen bonds, the disaccharides reduced this value for peptide-peptide interactions for 6N8C, while for 2LD2 sucrose and trehalose instead promoted an increase of this number. Such a difference in behaviors of peptides could be related to dissimilarities in their sequences, pointing out the importance to consider amino-acid residues in C- and N-terminal when developing drugs. Furthermore, both disaccharides demonstrated abilities to slow down the dynamics of simulated mixtures, which was concluded from rotational correlation and self-intermediate scattering functions. Amino-acid residues MET(1), GLU(5), LYS(6), LYS(9), GLU(12), LYS(15), PHE(17) and GLN(18) are identified as the main candidate amino acids involved in interpeptide binding and binding to disaccharides, where the glutamic acid residues (GLU(5) and GLU(12)) had the highest number of hydrogen bonds with sucrose and trehalose.