(192v) Scaling of Peptide Sequence-Dependent Hydrophobic Interactions from Experiment and Simulation

Hydrophobic interactions (HIs) drive structural transitions and self-assembly processes in many natural and synthetic systems. Past experimental investigations into the HI have probed macroscopic interfaces or indirectly investigated molecular-level details. In contrast, simulations have historically focused on HIs for microscopic, idealized systems. Here, we use both atomic force microscopy experiments and molecular dynamics simulations to directly probe the HI between peptides of controlled hydrophobic content and an extended hydrophobic self-assembled monolayer (SAM) surface. Specifically, a hydrophilic glycine-serine repeat scaffold is systematically modified to contain one to four leucine residues, which are allowed to interact with the SAM surface. Simulated systems closely mirror the experimental set-up, even employing the same non-equilibrium technique, specifically Jarzynski’s equality, to evaluate free energy differences. This constitutes a unique convergence of simulation and experiment in directly probing the HI on a molecular level for a realistic, soft-matter system. In addition to qualitatively agreeing with experiment, our simulations also identify key molecular structural factors driving the increase in the strength of the observed HI. While all peptides are relatively disordered in both solution and absorbed to surfaces, we observe differences in the tetrahedral structure of nearby water. We find that the three-body angle distributions of waters nearby solutes clearly distinguish between large and small scale hydrophobes, as well as hydrophobic and hydrophilic residues. As the hydrophobic content of a peptide increases, three-body angle distributions shift towards that of an isolated, small hydrophobe. Using these shifts as a metric, we construct an empirical model that well-predicts the free energy change of removing these peptides from the SAM surface. This work may be extended to probe the response of three-body angle distributions of water to various solutes and the ability of models based on this quantity to estimate solvation or interaction free energies.