Analysis of fast boundary-integral approximations for modeling electrostatic contributions of molecular binding.
We analyze and suggest improvements to a recently developed approximate continuum-electrostatic model for proteins. The model, called BIBEE/I (boundary-integral based electrostatics estimation with interpolation), was able to estimate electrostatic solvation free energies to within a mean unsigned error of 4% on a test set of more than 600 proteins-a significant improvement over previous BIBEE models. In this work, we tested the BIBEE/I model for its capability to predict residue-by-residue interactions in protein-protein binding, using the widely studied model system of trypsin and bovine pancreatic trypsin inhibitor (BPTI). Finding that the BIBEE/I model performs surprisingly less well in this task than simpler BIBEE models, we seek to explain this behavior in terms of the models' differing spectral approximations of the exact boundary-integral operator. Calculations of analytically solvable systems (spheres and tri-axial ellipsoids) suggest two possibilities for improvement. The first is a modified BIBEE/I approach that captures the asymptotic eigenvalue limit correctly, and the second involves the dipole and quadrupole modes for ellipsoidal approximations of protein geometries. Our analysis suggests that fast, rigorous approximate models derived from reduced-basis approximation of boundary-integral equations might reach unprecedented accuracy, if the dipole and quadrupole modes can be captured quickly for general shapes.
Department of Chemistry, Wellesley College, Wellesley MA 02481, USA.
Amelia B
AB
Kreienkamp
Department of Chemistry, Wellesley College, Wellesley MA 02481, USA.
Lucy Y
LY
Liu
Department of Chemistry, Wellesley College, Wellesley MA 02481, USA.
Mona S
MS
Minkara
Computation Institute, U. Chicago, Chicago IL 60637, USA.
Matthew G
MG
Knepley
Department of Electrical and Computer Engineering, Northeastern University, Boston MA 02115, USA.
Jaydeep P
JP
Bardhan
Department of Chemistry, Wellesley College, Wellesley MA 02481, USA.
Mala L
ML
Radhakrishnan
BIBEE; Component analysis; boundary-element methods; continuum solvation; implicit-solvent models; molecular electro-statics