Free energy perturbation (FEP) is becoming a widely used tool in drug design. However, the FEP calculations that have been presented do not account for protonation state changes in the prospective ligands and targets. Here we combine FEP, constant pH molecular dynamics (CpHMD), and the Wyman-Tanford linkage equation to compute the pH-dependent binding free energy of a drug candidate to both the beta-site amyloid precursor protein cleavage enzyme 1 (BACE1) and cathepsin D (CatD). CatD and BACE1 are similar aspartyl proteases with strongly pH-dependent activities. Although BACE1 is a target of Alzheimer's drug discovery, inhibiting CatD (an off-target of BACE1) is undesirable, as doing so leads to retinal damage. The pH-dependent binding free energies computed here correctly predict that the drug candidate has a preference of about 1.0 kcal/mol for BACE1 over CatD. Additionally, the CpHMD results reveal a histidine residue far from the binding pocket that modulates the pH-dependent binding free energy through an allosteric mechanism. The presented techniques will be useful in the design of drugs for other pH-sensitive targets.

Using constant pH molecular dynamics and free energy perturbation to compute ph-dependent binding free energies

254th National Meeting (2017)

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