Qichao Wei, Weilong Zhao, Yang Yang, Beiliang Cui, Zhijun Xu, Xiaoning Yang

Considerable interest in characterizing the protein/peptide-surface interactions, has prompted extensive computational studies on calculations of adsorption free energy. However, in many cases, each individual study has focused on application of free energy calculations to a specific system, therefore, it is difficult to combine the results into a general picture for pre-choosing an appropriate strategy for the system of interest. In our present study, we systemically compared and evaluated three well-established computational algorithms to compute the adsorption free energy of small molecules on two representative surfaces. Our results clearly demonstrated that the characteristics of studied interfacial systems have crucial effects on the accuracy and efficiency of the adsorption free energy calculations. For the hydrophobic surface, steered molecular dynamics exhibits the highest efficiency, appearing to be a favorable method of choice for enhanced sampling simulations. However, for the charged surface, only the umbrella sampling method has the ability to accurately explore the adsorption free energy surface. The affinity of the water layer to the surface significantly affects the performance of free energy calculation methods, especially at the region close to the surface. Therefore, we attempt to propose a general principle of how to discriminate between methodological and sampling issues based on the interfacial characteristics of the system under investigation.