What determines the van der Waals coefficient β in the LIE (linear interaction energy) method to estimate binding free energies using molecular dynamics simulations?

Recently a semiempirical method has been proposed by Åqvist et al. 1 , 2 , 3 to calculate absolute and relative binding free energies. In this method, the absolute binding free energy of a ligand is estimated as ΔGbind = α〈V  boundel − V  freeel 〉 + β〈V  boundvdw − V  freevdw , where V  boundel and V  boundvdw are the electrostatic and van der Waals interaction energies between the ligand and the solvated protein from an molecular dynamics (MD) trajectory with ligand bound to protein and V  freeel and V  freevdw are the electrostatic and van der Waals interaction energies between the ligand and the water from an MD trajectory with the ligand in water. A set of values, α = 0.5 and β = 0.16, was found to give results in good agreement with experimental data. Later, however, different optimal values of β were found in studies of compounds binding to P450cam 4 and avidin. 5 The present work investigates how the optimal value of β depends on the nature of binding sites for different protein‐ligand interactions. By examining seven ligands interacting with five proteins, we have discovered a linear correlation between the value of β and the weighted non‐polar desolvation ratio (WNDR), with a correlation coefficient of 0.96. We have also examined the ability of this correlation to predict optimal values of β for different ligands binding to a single protein. We studied twelve neutral compounds bound to avidin. In this case, the WNDR approach gave a better estimate of the absolute binding free energies than results obtained using the fixed value of β found for biotin‐avidin. In terms of reproducing the relative binding free energy to biotin, the fixed‐β value gave better results for compounds similar to biotin, but for compounds less similar to biotin, the WNDR approach led to better relative binding free energies. Proteins 1999;34:395–402. © 1999 Wiley‐Liss, Inc.

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