In the absence of experimental assignments, the empirical charge/hydropathy correlation for the prediction of natively unfolded protein sequences (Uversky, V. N.; Gillespie, J. R.; Fink, A. L. Proteins: Struct., Funct., Genet. 2000, 41, 415-427) provides perhaps the most intuitive description of gross polypeptide conformation. The success of this correlation rests on an essential chain length independence of the boundary line between expanded and compact conformations, conversely stabilized by highly charged/weakly hydrophobic residues or weakly charged/highly hydrophobic residues, respectively. We present extensive simulation results for coarse-grained polypeptides over a wide range of sequence hydrophobicities, charges, and lengths. A coil-to-globule transition in sequence composition space analogous to the charge/hydropathy correlation is observed. A near sequence length independent stability boundary is only found when counterions for the charged peptides are explicitly included, as a result of counterion condensation stabilization of repulsive electrostatic interactions on the globule surface. The observed counterion adsorption is shown to be in quantitative agreement with theoretical condensation predictions. We argue that alternate functionalities, beyond charge and hydrophobicity, empirically known to correlate with conformational disorder can be incorporated into our minimalist polypeptide model to study the interplay between independent predictors of unfolded sequences.

Following the conclusions of an information theory analysis that hydrophobic hydration is dictated by the equation of state of liquid water, we perform simulations of ten different water models to examine the correlation between the fidelity of each model to the experimental density of liquid water and the accuracy of its description of methane hydration. We find that the three- and five-point water models provide an inferior description of both the liquid density and methane solubility compared to the four-point water models. Of the four-point water models, TIP4P/2005 provides the best description of both the aqueous equation-of-state and methane hydration thermodynamics. When the optimized potentials for liquid simulation united-atom description for methane is used, we find that while the entropy and heat capacity of methane hydration are in excellent agreement with experiment, the chemical potential and enthalpy are systematically shifted upwards. We subsequently reoptimize the methane interaction to accurately reproduce the experimental solubilities as a function of temperature by accounting for missing attractive interactions.

Although hot, cold, and high pressure denaturation are well characterized, the possibility of negative pressure unfolding has received much less attention. Proteins under negative pressure, however, are important in applications such as medical ultrasound, and the survival of biopoloymers in the xylem and adjacent parenchyma cells of vascular plants. In addition, negative pressure unfolding is fundamentally important in obtaining a complete understanding of protein stability and naturally complements previous studies of high pressure denaturation. We use extensive replica-exchange molecular dynamics (REMD) simulations and thermodynamic analysis to obtain folding/unfolding equilibrium phase diagrams for the miniprotein trp-cage (α-structure, 20-residue), the GB1 β-hairpin (β-structure, 16-residue), and the AK16 peptide (α-helix, 16-residue). Although the trp-cage is destabilized by negative pressure, the GB1 β-hairpin and AK16 peptide are stabilized by this condition.

The fluid phase diagram of trimer particles composed of one central attractive bead and two repulsive beads was determined as a function of simple geometric parameters using flat-histogram Monte Carlo methods. A variety of self-assembled structures were obtained including spherical micelle-like clusters, elongated clusters, and densely packed cylinders, depending on both the state conditions and shape of the trimer. Advanced simulation techniques were employed to determine transitions between self-assembled structures and macroscopic phases using thermodynamic and structural definitions. Simple changes in particle geometry yield dramatic changes in phase behavior, ranging from macroscopic fluid phase separation to molecular-scale self-assembly. In special cases, both self-assembled, elongated clusters and bulk fluid phase separation occur simultaneously. Our work suggests that tuning particle shape and interactions can yield superstructures with controlled architecture.

The Free Energy and Advanced Sampling Simulation Toolkit (FEASST) is a free, open-source, modular program to conduct molecular and particle-based simulations with Metropolis, Wang-Landau, and Transition-Matrix Monte Carlo methods. FEASST is implemented in C++ and may be imported as a module within Python 2 or 3. This document describes the initial public release version 1.0.