Structure-wise discrimination of cytosine, thymine, and uracil by proteins in terms of their nonbonded interactions

Abstract

The molecular recognition and discrimination of very similar ligand moieties by proteins are important subjects in protein-ligand interaction studies. Specificity in the recognition of molecules is determined by the arrangement of protein and ligand atoms in space. The three pyrimidine bases, viz. cytosine, thymine, and uracil, are structurally similar, but the proteins that bind to them are able to discriminate them and form interactions. Since nonbonded interactions are responsible for molecular recognition processes in biological systems, our work attempts to understand some of the underlying principles of such recognition of pyrimidine molecular structures by proteins. The preferences of the amino acid residues to contact the pyrimidine bases in terms of nonbonded interactions; amino acid residue-ligand atom preferences; main chain and side chain atom contributions of amino acid residues; and solvent-accessible surface area of ligand atoms when forming complexes are analyzed. Our analysis shows that the amino acid residues, tyrosine and phenyl alanine, are highly involved in the pyrimidine interactions. Arginine prefers contacts with the cytosine base. The similarities and differences that exist between the interactions of the amino acid residues with each of the three pyrimidine base atoms in our analysis provide insights that can be exploited in designing specific inhibitors competitive to the ligands.

Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway

“…In recent years, uridine, uracil, and thymine (2, 3, and 4, Figure 1) have attracted much interest due to their promising potential biological activities, and their modified derivatives have exhibited excellent activities, such as antibacterial, inhibition against 1,4-β-galactosyltransferase, antivirus, anticancer, and so on [29][30][31][32][33][34][35][36]. Our previous studies [37,38] have also shown that uridine/uracil/thymine attached to the natural compound oleanolic acid could afford derivatives that possess high anti-proliferative activities against tumor cell lines and exhibit clearly inducing effects on cell apoptosis.…”

A multi-scale time-resolved study of photoactivated dynamics in 5-benzyl uracil, a model for DNA/protein interactions

“…Indeed, a statistical survey of the X-ray protein structure shows that the majority of the pyrimidine bases interacting with a protein exhibit close contact (often involving pp stacking) with the side chain of a phenylalanine (a benzene ring) or of a tyrosine (a phenol ring). 30 Recent theoretical studies, using the multireference selfconsistent field (state-averaged CASSCF) method, of the photophysics and photochemistry of a single base 31 and the steadystate optical response of 5BU 32,33 confirm the extreme interest of this system in many respects. In fact, the first and second singlet excited-states of 5BU identified possible relaxation pathways on the Potential Energy Surfaces (PESs) of the molecule, different from the pathways found for the individual moieties of uracil and benzene.…”