title: FAMBE-pH: a fast and accurate method to compute the total solvation free energies of proteins.
abstract: A fast and accurate method to compute the total solvation free energies of proteins as a function of pH is presented. The method makes use of a combination of approaches, some of which have already appeared in the literature; (i) the Poisson equation is solved with an optimized fast adaptive multigrid boundary element (FAMBE) method; (ii) the electrostatic free energies of the ionizable sites are calculated for their neutral and charged states by using a detailed model of atomic charges; (iii) a set of optimal atomic radii is used to define a precise dielectric surface interface; (iv) a multilevel adaptive tessellation of this dielectric surface interface is achieved by using multisized boundary elements; and (v) 1:1 salt effects are included. The equilibrium proton binding/release is calculated with the Tanford-Schellman integral if the proteins contain more than approximately 20-25 ionizable groups; for a smaller number of ionizable groups, the ionization partition function is calculated directly. The FAMBE method is tested as a function of pH (FAMBE-pH) with three proteins, namely, bovine pancreatic trypsin inhibitor (BPTI), hen egg white lysozyme (HEWL), and bovine pancreatic ribonuclease A (RNaseA). The results are (a) the FAMBE-pH method reproduces the observed pK a's of the ionizable groups of these proteins within an average absolute value of 0.4 p K units and a maximum error of 1.2 p K units and (b) comparison of the calculated total pH-dependent solvation free energy for BPTI, between the exact calculation of the ionization partition function and the Tanford-Schellman integral method, shows agreement within 1.2 kcal/mol. These results indicate that calculation of total solvation free energies with the FAMBE-pH method can provide an accurate prediction of protein conformational stability at a given fixed pH and, if coupled with molecular mechanics or molecular dynamics methods, can also be used for more realistic studies of protein folding, unfolding, and dynamics, as a function of pH.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Science, Novosibirsk, Russia.
authors.forename: Yury N
authors.initials: YN
authors.lastname: Vorobjev
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Vila
authors.forename: Harold A
authors.initials: HA
authors.lastname: Scheraga
mesh_terms: D000465:Algorithms; D000818:Animals; D002417:Cattle; D004553:Electric Conductivity; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D012259:Ribonuclease, Pancreatic / Q000737:chemistry; D012680:Sensitivity and Specificity; D012997:Solvents / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D011506:Proteins; D012997:Solvents; D012259:Ribonuclease, Pancreatic; C421864:hen egg lysozyme; D009113:Muramidase