NTL9 Folding at Constant pH: The Importance of Electrostatic Interaction and pH Dependence

• Published in: Journal of chemical theory and computation 2016-07, Vol.12 (7), p.3270-3277
• Main Authors: Contessoto, Vinícius G, de Oliveira, Vinícius M, de Carvalho, Sidney J, Oliveira, Leandro C, Leite, Vitor B. P
• Format: Article
• Language: English
• Subjects: Computer simulation; Constants; Denaturation; Electrostatics; Folding; Free energy; Hydrogen-Ion Concentration; Mathematical models; Models, Molecular; Protein Folding - drug effects; Static Electricity
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.6b00399

The folding process of the N-terminal domain of ribosomal protein L9 (NTL9) was investigated at constant-pH computer simulations. Evaluation of the role of electrostatic interaction during folding was carried out by including a Debye–Hückel potential into a C α structure-based model (SBM). In this study, the charges of the ionizable residues and the electrostatic potential are susceptible to the solution conditions, such as pH and ionic strength, as well as to the presence of charged groups. Simulations were performed under different pHs, and the results were validated by comparing them with experimental values of pK a and with denaturation experiment data. Also, the free energy profiles, Φ-values, and folding routes were calculated for each condition. It was shown how charges vary along the folding under different pH, which is subject to different scenarios. This study reveals how simplified models can capture essential physical features, reproducing experimental results, and presenting the role of electrostatic interactions before, during, and after the transition state.