Alchemical-transfer FEP with enhanced sampling shows a charged nuclear-localization peptide binds importin-α through water and ion release entropy
- Alchemical transfer FEP swaps a bound and an unbound peptide, avoiding net-charge corrections, and was combined with replica exchange solute tempering and a soft flat-bottom restraint.
- Applied to a charged viral nuclear-localization peptide binding importin-α, it sampled binding thoroughly with small statistical error.
- Isothermal titration calorimetry agreed moderately with the computed affinity.
- Decomposition showed unfavorable net enthalpy from interfacial water and ion expulsion, offset by entropy gain: binding is entropy-driven.
💡 Points Based on the abstract
A single importin-α/NLS system with only moderate ITC agreement is one data point and does not establish the protocol. The entropy-driven reading depends on a water and ion decomposition that shifts with force field and ion parameters. Compare the computed enthalpy directly with calorimetry, and benchmark against standard double decoupling or MM-GBSA on the same system.