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Abstract Variational implicit solvation models (VISMs) have gained extensive popularity in the molecular-level solvation analysis of biological systems due to their cost-effectiveness and satisfactory accuracy. Central in the construction of VISM is an interface separating the solute and the solvent. However, traditional sharp-interface VISMs fall short in adequately representing the inherent randomness of the solute–solvent interface, a consequence of thermodynamic fluctuations within the solute–solvent system. Given that experimentally observable quantities are ensemble averaged, the computation of the ensemble average solvation energy (EASE)–the averaged solvation energy across all thermodynamic microscopic states–emerges as a key metric for reflecting thermodynamic fluctuations during solvation processes. This study introduces a novel approach to calculating the EASE. We devise two diffuse-interface VISMs: one within the classic Poisson–Boltzmann (PB) framework and another within the framework of size-modified PB theory, accounting for the finite-size effects. The construction of these models relies on a new diffuse interface definition $u\left(x\right)$u\left(x), which represents the probability of a point $x$xfound in the solute phase among all microstates. Drawing upon principles of statistical mechanics and geometric measure theory, we rigorously demonstrate that the proposed models effectively capture EASE during the solvation process. Moreover, preliminary analyses indicate that the size-modified EASE functional surpasses its counterpart based on the classic PB theory across various analytic aspects. Our work is the first step toward calculating EASE through the utilization of diffuse-interface VISM. 

Protein structures at solid/liquid interfaces mediate interfacial protein functions, which are important for many applications. It is difficult to probe interfacial protein structures at buried solid/liquid interfaces in situ at the molecular level. Here, a systematic methodology to determine protein molecular structures (orientation and conformation) at buried solid/liquid interfaces in situ was successfully developed with a combined approach using a nonlinear optical spectroscopic technique – sum frequency generation (SFG) vibrational spectroscopy, isotope labeling, spectra calculation, and computer simulation. With this approach, molecular structures of protein GB1 and its mutant (with two amino acids mutated) were investigated at the polymer/solution interface. Markedly different orientations and similar (but not identical) conformations of the wild-type protein GB1 and its mutant at the interface were detected, due to the varied molecular interfacial interactions. This systematic strategy is general and can be widely used to elucidate protein structures at buried interfaces in situ . 

This paper summarizes the early research results on studying proteins and peptides at interfaces using sum frequency generation (SFG) vibrational spectroscopy. SFG studies in the C—H stretching frequency region to examine the protein side-chain behavior and in the amide I frequency region to investigate the orientation and conformation of interfacial peptides/proteins are presented. The early chiral SFG research and SFG isotope labeling studies on interfacial peptides/proteins are also discussed. These early SFG studies demonstrate the feasibility of using SFG to elucidate interfacial molecular structures of peptides and proteins in situ, which built a foundation for later SFG investigations on peptides and proteins at interfaces.