Fast estimation of protein conformational preference at air/water interface via molecular dynamics simulations

Understanding the protein structural stability and thus its functional integrity at interface are critical for its biotechnology application development. Conventionally, it requires two extensive free energy calculations of protein in bulk and at interface to evaluate the conformational preference change during the adsorption. In this work, we derive an estimation of adsorption free energy at air/water interface for a protein in a defined conformation with the contributions of partial desolvation ΔG_desolv and surface energy ΔG_a/w, which can be quickly evaluated from equilibrium MD trajectories. Via thermodynamics cycle, the free energy variation of α-helix to β-hairpin transition during the adsorption ΔΔG_wat→int ^α→β can be obtained from the difference between the adsorption free energies of the two conformations. Applying the method, we estimate ΔΔG_wat→int ^α→β of 6.31kJ/mol for DP5, in excellent agreement with the MD free energy data of 6.35 kJ/mol. Consistent results for four other tested proteins compared with MD free energy calculation further validate the derived adsorption model. The combination of MD simulations and thermodynamic estimations provide valuable physical insights for protein interfacial folding behaviors and serve as basis for developing prediction tools of protein conformations at interface.