Quantum Mechanical Binding Free-energy Calculation for Phosphopeptide Inhibitors of the Lck SH2 Domain

ANISIMOV, VICTOR M.; CAVASOTTO, CLAUDIO N.

JOURNAL OF COMPUTATIONAL CHEMISTRY

JOHN WILEY & SONS INC

Año: 2011 vol. 32 p. 2254 - 2263

0192-8651

The accurate and efficient calculation of binding free energies is essential in computational biophysics.  We present a linear-scaling quantum mechanical (QM)-based end-point method termed MM/QM-COSMO to calculate binding free energies in biomolecular systems, with an improved description of entropic changes.  Molecular dynamics trajectories are re-evaluated using a semiempirical Hamiltonian and a continuum solvent model; translational and rotational entropies are calculated using configurational integrals, and internal entropy is calculated using the harmonic oscillator approximation.  As an application, we studied the binding of a series of phosphotyrosine tetrapeptides to the human Lck SH2 domain, a key component in intracellular signal transduction, and which modulation can have therapeutic relevance in the treatment of cancer, osteoporosis, and autoimmune diseases.  Calculations with molecular mechanics Poisson-Boltzmann, and generalized Born surface area methods showed large discrepancies with experimental data stemming from the enthalpic component, in agreement with an earlier report.  The empirical force field-based solvent interaction energy (SIE) scoring function yielded improved resuls, with average unsigned error of 3.6 kcal/mol, and a better ligand ranking.  The MM/QM-COSMO method exhibited the best agreement both for absolute (average unsigned error = 0.7 kcal/mol), and relative binding free energy calculations.  These results show the feasibility and promise of a full QM-based end-point method with an adequate balance of accuracy and computational efficiency.