Solute–Solvent Energetics Based on Proximal Distribution Functions

We consider the hydration structure and thermodynamic energetics of solutes in aqueous solution. On the basis of the dominant local correlation between the solvent and the chemical nature of the solute atoms, proximal distribution functions (pDF) can be used to quantitatively estimate the hydration pattern of the macromolecules. We extended this technique to study the solute–solvent energetics including the van der Waals terms representing excluded volume and tested the method with butane and propanol. Our results indicate that the pDF-reconstruction algorithm can reproduce van der Waals solute–solvent interaction energies to useful kilocalorie per mole accuracy. We subsequently computed polyalanine–water interaction energies for a variety of conformers, which also showed agreement with the simulated values

Protein Denaturants at Aqueous–Hydrophobic Interfaces: Self-Consistent Correlation between Induced Interfacial Fluctuations and Denaturant Stability at the Interface

The notion of direct interaction between denaturing cosolvent and protein residues has been proposed in dialogue relevant to molecular mechanisms of protein denaturation. Here we consider the correlation between free energetic stability and induced fluctuations of an aqueous–hydrophobic interface between a model hydrophobically associating protein, HFBII, and two common protein denaturants, guanidinium cation (Gdm⁺) and urea. We compute potentials of mean force along an order parameter that brings the solute molecule close to the known hydrophobic region of the protein. We assess potentials of mean force for different relative orientations between the protein and denaturant molecule. We find that in both cases of guanidinium cation and urea relative orientations of the denaturant molecule that are parallel to the local protein–water interface exhibit greater stability compared to edge-on or perpendicular orientations. This behavior has been observed for guanidinium/methylguanidinium cations at the liquid–vapor interface of water, and thus the present results further corroborate earlier findings. Further analysis of the induced fluctuations of the aqueous–hydrophobic interface upon approach of the denaturant molecule indicates that the parallel orientation, displaying a greater stability at the interface, also induces larger fluctuations of the interface compared to the perpendicular orientations. The correlation of interfacial stability and induced interface fluctuation is a recurring theme for interface-stable solutes at hydrophobic interfaces. Moreover, observed correlations between interface stability and induced fluctuations recapitulate connections to local hydration structure and patterns around solutes as evidenced by experiment (Cooper et al., <i>J. Phys. Chem. A</i> <b>2014</b>, <i>118</i>, 5657.) and high-level ab initio/DFT calculations (Baer et al., <i>Faraday Discuss</i> <b>2013</b>, <i>160</i>, 89)

Nonpolar Solvation Free Energy from Proximal Distribution Functions

Using precomputed near neighbor or proximal distribution functions (pDFs) that approximate solvent density about atoms in a chemically bonded context one can estimate the solvation structures around complex solutes and the corresponding solute–solvent energetics. In this contribution, we extend this technique to calculate the solvation free energies (Δ<i>G</i>) of a variety of solutes. In particular we use pDFs computed for small peptide molecules to estimate Δ<i>G</i> for larger peptide systems. We separately compute the non polar (Δ<i>G</i>_vdW) and electrostatic (Δ<i>G</i>_elec) components of the underlying potential model. Here we show how the former can be estimated by thermodynamic integration using pDF-reconstructed solute–solvent interaction energy. The electrostatic component can be approximated with Linear Response theory as half of the electrostatic solute–solvent interaction energy. We test the method by calculating the solvation free energies of butane, propanol, polyalanine, and polyglycine and by comparing with traditional free energy simulations. Results indicate that the pDF-reconstruction algorithm approximately reproduces Δ<i>G</i>_vdW calculated by benchmark free energy simulations to within ∼ kcal/mol accuracy. The use of transferable pDFs for each solute atom allows for a rapid estimation of Δ<i>G</i> for arbitrary molecular systems