Prediction of protein solubility from calculation of transfer free energy.

Abstract:

:Solubility plays a major role in protein purification, and has serious implications in many diseases. We studied the effects of pH and mutations on protein solubility by calculating the transfer free energy from the condensed phase to the solution phase. The condensed phase was modeled as an implicit solvent, with a dielectric constant lower than that of water. To account for the effects of pH, the protonation states of titratable side chains were sampled by running constant-pH molecular dynamics simulations. Conformations were then selected for calculations of the electrostatic solvation energy: once for the condensed phase, and once for the solution phase. The average transfer free energy from the condensed phase to the solution phase was found to predict reasonably well the variations in solubility of ribonuclease Sa and insulin with pH. This treatment of electrostatic contributions combined with a similar approach for nonelectrostatic contributions led to a quantitative rationalization of the effects of point mutations on the solubility of ribonuclease Sa. This study provides valuable insights into the physical basis of protein solubility.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Tjong H,Zhou HX

doi

10.1529/biophysj.107.127746

subject

Has Abstract

pub_date

2008-09-15 00:00:00

pages

2601-9

issue

6

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(08)78406-6

journal_volume

95

pub_type

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