The hydration free energies of ions exhibit an approximately quadratic dependence on the ionic charge, as predicted by the Born model. We analyze this behavior using second-order perturbation theory. This provides effective methods to calculating free energies from equilibrium computer simulations. The average and the fluctuation of the electrostatic potential at charge sites appear as the first coefficients in a Taylor expansion of the free energy of charging. Combining the data from different charge states (e.g., charged and uncharged) allows calculation of free-energy profiles as a function of the ionic charge. The first two Taylor coefficients of the free-energy profiles can be computed accurately from equilibrium simulations; but they are affected by a strong system-size dependence. We apply corrections for these finite-size effects by using Ewald lattice summation and adding the self-interactions consistently. An analogous procedure is used for reaction-field electrostatics. Results are presented for a model ion with methane-like Lennard-Jones parameters in SPC water. We find two very closely quadratic regimes with different parameters for positive and negative ions. We also studied the hydration free energy of potassium, calcium, fluoride, chloride, and bromide ions. We find negative ions to be solvated more strongly (as measured by hydration free energies) compared to positive ions of equal size, in agreement with experimental data. We ascribe this preference of negative ions to their strong interactions with water hydrogens, which can penetrate the ionic van der Waals shell without direct energetic penalty in the models used. In addition, we consistently find a positive electrostatic potential at the center of uncharged Lennard-Jones particles in water, which also favors negative ions. Regarding the effects of a finite system size, we show that even using only 16 water molecules it is possible to calculate accurately the hydration free energy of sodium if self-interactions are considered.

A molecular model of poorly understood hydrophobic effects is heuristically developed using the methods of information theory. Because primitive hydrophobic effects can be tied to the probability of observing a molecular-sized cavity in the solvent, the probability distribution of the number of solvent centers in a cavity volume is modeled on the basis of the two moments available from the density and radial distribution of oxygen atoms in liquid water. The modeled distribution then yields the probability that no solvent centers are found in the cavity volume. This model is shown to account quantitatively for the central hydrophobic phenomena of cavity formation and association of inert gas solutes. The connection of information theory to statistical thermodynamics provides a basis for clarification of hydrophobic effects. The simplicity and flexibility of the approach suggest that it should permit applications to conformational equilibria of nonpolar solutes and hydrophobic residues in biopolymers.Hydrophobic interactions are widely believed to be of dominating importance for protein structure, aggregation, and function. However, the molecular theories of hydrophobic interactions (1-10) have not been used so far in molecular studies of protein structure. This is partly because these theories have limitations that are still being clarified (5,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) and partly because of their complexity. This paper suggests a new approach to molecular theories of hydrophobic effects and then tests the simplest model to which this suggestion leads. It is argued that the simplicity and flexibility of this approach should eventually permit its application to issues of protein structure in solution.Alternative descriptions of hydrophobic effects that are used are based upon parameterizations of solubility data (22)(23)(24)(25)(26). Those hydrophobicity models have not changed essentially from the concepts of Kauzmann (27) but the solubility data have been parameterized in a variety of ways (28-31). Although solubility models of hydrophobic effects have been useful, molecular-level theories are expected to have wider applicability and to improve our understanding of hydrophobic effects on biomolecular structure. This could be particularly important to recent work that probes protein solution structure in new ways.One example of such work is reversible denaturation experiments. The observed destabilization of folded proteins with decreasing temperature is an evidence of hydrophobic interactions. Cold/heat denaturation of globular proteins (32-34), pressure denaturation (35-39), and the effects of osmotic stress (40)(41)(42)(43)(44)(45)(46)(47)(48)(49) demonstrate that the solvent activity affects the structure. However, parameterizations of hydrophobicity models that reflect the activity of the aqueous medium have not been pursued extensively (50).The adequacy of solubility models is also not obvious in studies of the structures of folding intermediates on renaturation pathways. These stu...

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SummaryThe role of two peptides, Aβ40 and Aβ42 in the early pathogenesis of the Alzheimer's disease (AD) is frequently emphasized in the literature. It is known that Aβ42 is more prone to aggregation than Aβ40, even though they only differ in two (IA) amino acid residues at the C-terminal end. A direct comparison of the ensembles of conformations adopted by the monomers in solution has been limited by the inherent flexibility of the unfolded peptides. Here we characterize the conformations of Aβ40 and Aβ42 in water by using a combination of molecular dynamics (MD) and measured scalar 3 J HNHα data from NMR experiments. We perform replica exchange MD (REMD) simulations and find that classical forcefields quantitatively reproduce the NMR data when the sampling is extended to the microseconds time scale. Using the quantitative agreement of the NMR data as a validation of the model, we proceed to compare the conformational ensembles of the Aβ40 and Aβ42 peptide monomers. Our analysis confirms the existence of structured regions within the otherwise flexible Aβ peptides. We find that the C-terminus of Aβ42 is more structured than that of Aβ40. The formation of a β-hairpin in the sequence 31 IIGLMVGGVVIA involving short strands at residues 31−34 and 38−41 reduces the C-terminal flexibility of the Aβ42 peptide and may be responsible for the higher propensity of this peptide to form amyloids. KeywordsAlzheimer's disease; Amyloid-β peptides; conformational ensemble; replica exchange molecular dynamics; J-coupling constants Two peptides have received tremendous interest in modern Alzheimer's disease (AD) research. Aβ40 and 42 are major products of the proteolytic cleavage of a multi-domain integral membrane type I protein, Amyloid-β Precursor Protein (APP), whose functions include cell adhesion, neuronal mobility and transcriptional regulation 1 . APP metabolism includes processing by a group of dedicated proteases, named secretases, in two known pathways to yield intracellular and extracellular fragments with a broad range of functions in synaptic transmission and neuronal plasticity 2 . During the amyloidogenic pathway, the action of β and subsequently γ secretase yields the Aβ peptides. The exact location of the transmembrane cleavage site for γ secretase results in a variability in the length of its Aβ product from 38 to 43 residues, however lengths of 40 and 42 are the dominant species. The physiological role of the Aβ peptides in vivo remains unclear. Aβ40 has been proposed to regulate the activity of K + channels 3 and also to modulate synaptic transmission 4 , however the mechanisms upon it * To whom correspondence should be addressed angel@rpi.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production p...

Water is an essential participant in the stability, structure, dynamics, and function of proteins and other biomolecules. Thermodynamically, changes in the aqueous environment affect the stability of biomolecules. Structurally, water participates chemically in the catalytic function of proteins and nucleic acids and physically in the collapse of the protein chain during folding through hydrophobic collapse and mediates binding through the hydrogen bond in complex formation. Water is a partner that slaves the dynamics of proteins, and water interaction with proteins affect their dynamics. Here we provide a review of the experimental and computational advances over the past decade in understanding the role of water in the dynamics, structure, and function of proteins. We focus on the combination of X-ray and neutron crystallography, NMR, terahertz spectroscopy, mass spectroscopy, thermodynamics, and computer simulations to reveal how water assist proteins in their function. The recent advances in computer simulations and the enhanced sensitivity of experimental tools promise major advances in the understanding of protein dynamics, and water surely will be a protagonist.