The shift in urea orientation at protein surfaces at low pH is compatible with a direct mechanism of protein denaturation

Author(s)

de Oliveira, Ivan Pires ^{[1, 2, 3]} ; Martinez, Leandro ^{[1, 3]}

Affiliation

^[1] Univ Estadual Campinas, Inst Chem, BR-13083970 Campinas, SP - Brazil

^[2] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Ctr Comp Engn & Sci, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: Physical Chemistry Chemical Physics; v. 22, n. 1, p. 354-367, JAN 7 2020.
• Web of Science Citations: 0

Abstract

Surface-specific spectroscopic data has shown that urea undergoes a shift in orientation at protein surfaces in acidic media. Since urea denatures proteins at a wide range of pHs, the variable chemical nature of protein-urea interactions has been used to support an indirect mechanism of urea-induced denaturation. Here, we use molecular dynamics simulations, minimum-distance distribution functions (MDDFs), and hydrogen-bond analysis, to characterize the interactions of urea with proteins at neutral and low pH, as defined by the protonation state of acidic residues. We obtain the expected preferential solvation by urea and dehydration, consistently with urea-induced denaturation, while the MDDFs allow for a solvent-shell perspective of protein-urea interactions. The distribution functions are decomposed into atomic contributions to show that there is indeed a shift in the orientation of urea molecules in the vicinity of acidic side-chains, as shown by the experimental spectroscopic data. However, this effect is local, and the interactions of urea with the other side chains and with the protein backbone are essentially unaffected at low pH. Therefore, hydrophobic solvation and urea-backbone hydrogen bonds can play a role in a direct mechanism of urea-induced protein denaturation without contradicting the observed variations in the chemical nature of protein-urea interactions as a function of the acidity of the solution. (AU)

• FAPESP's process: 17/02201-4 - Study of the inhibition of the accumulation of cyclic nucleotide by pyridopyrimidine derivatives using molecular dynamics simulations
• Grantee: Ivan Pires de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/24293-0 - Computational methods in optimization
• Grantee: Sandra Augusta Santos
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/16947-9 - Correlations between dynamics, structure and function in protein: computer simulations and algorithms
• Grantee: Leandro Martinez
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/08293-7 - CCES - Center for Computational Engineering and Sciences
• Grantee: Munir Salomao Skaf
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC