Abstract

The properties of many biomolecules in solution are significantly altered in the presence of additional cosolvents. However, even though these effects have been known for over 100 years and has been quantified, an atomic level description of the interaction of cosolvents with peptides and proteins has still eluded researchers. As a first step to provide such a description we propose to study the effects of cosolvents of the hydration properties of small nonpolar molecules in pure water. Atomic level detail will be obtained using classical all atom molecular dynamics simulations. Nonpolar molecules to be studied include; He, Ne, Ar and methane. Cosolvents to be studied include; NaCl, (NH4)2SO4, urea, TFE and GdmHCl. Preliminary results show that molecular dynamics simulations coupled with Widom particle insertion techniques reproduce experimental salting out constants and are therefore capable of providing a quantitative description of the action of cosolvents on the solvation properties of nonpolar molecules in solution. Further studies are proposed which will extend this initial work to investigate the effects of i) variations in cosolvent concentration, ii) variations in temperature, iii) a wider variety of cosolvents, and iv) a determination of the importance of polarization effects within these systems. It is envisioned that the results obtained from the above studies will provide a consistent picture of the action of cosolvents on the properties of nonpolar molecules which will have a direct bearing on our understanding of hydrophobic aggregation, protein denaturation, and protein stabilization.

As part of a continuing effort to understand the conformational preferences of small peptides in both pure water and water plus cosolvent, we have been developing a reduced description of peptide/protein interactions based on a potential of mean force (pmf) approach. Our initial work, and that of others, has demonstrated that the pmf approach is a powerful technique for reducing the computational expense of traditional explicit solvent all atom simulations; thus providing the opportunity to study peptides on longer (microsecond) timescales. Such an approach requires i) an accurate description of the assumed pairwise interactions between the various functional groups common in peptides and proteins, and ii) the inclusion of many body effects, such as the tendency for hydrophobic aggregation, which are difficult to model with simple pairwise interactions. In order to model hydrophobic aggregation one has to understand the role of hydrophobic hydration of nonpolar solutes at the atomic level. As atomic level detail is one of the major advantages of modern day molecular dynamics (MD) simulations, we are currently using all atom simulations to investigate the effects of specific cosolvents on the hydrophobic hydration of small nonpolar molecules. Our specific aims are:

1. To determine the effects of cosolvents on the hydration properties of nonpolar molecules in solution. Using MD simulations to explore the nature and degree of hydration of nonpolar molecules (He, Ne, Ar, CH4, C6H6, etc) in the presence of different cosolvents ((NH4)2SO4, urea, GdmHCl, TFE, NaCl, etc). To determine how the hydration of nonpolar molecules varies with temperature and cosolvent concentration. To determine enthalpic and entropic contributions to the hydration process

2. To investigate the contribution of polarization effects to the solvation properties of nonpolar molecules in solution. Performing classical MD simulations including polarization effects using the induced dipole method to compare and contrast with explicit effective pair potentials. To determine the magnitude and directionality (salting in or out) of individual polarization effects.

3. To provide a link between a physical picture of cosolvent exclusion from or binding to nonpolar molecules in solution and the thermodynamic salting in/out constant of the cosolvent. By developing a clear picture of cosolvent effects at the atomic level and attempting to correlate the degree of preferential binding of either water or cosolvent with salting in/out ability.

Abstract

The removal of hazardous organic pollutants from the environment is a major DOE undertaking which requires the development of new or improved separation techniques. Many of the common pollutants are small nonpolar organic molecules which are only sparingly soluble in water. This solubility can be increased or decreased by the addition of different salts. The proposed research is aimed at understanding the interactions between benzene (a model nonpolar organic molecule) and both water and salt ions at the atomic level. This information will in turn lead to improved theories of salt effects and the possibility of designing solutions with specific salting in/out properties. Molecular dynamics simulations using both serial and parallel computers will be performed to obtain the atomic level detail necessary for a complete understanding of these interactions and how they affect the aggregation properties, and hence solubility, of nonpolar molecules in solution. Our initial studies will focus on benzene in i) water, ii) 2.0M sodium sulfate (strong salting out salt), iii) 2.0M sodium bromide (weak/neutral salting out salt) and iii) 2.0M tetramethylammonium bromide (salting in salt).

1. To provide an atomic level description of the interactions between benzene, water and ions in solution. Performing molecular dynamics simulations to determine; i) the probability of finding an anion or cation associated with a benzene molecule, and ii) the chemical potential of benzene in aqueous and salt solutions using thermodynamic integration techniques. To distinguish between nonspecific (surface tension increase, dielectric decrement) salt effects and specific benzene-ion associations. To quantify the degree of nonadditivity of anion and cation contributions to the observed salt effects.

2. To determine the degree of association between two benzene molecules in aqueous and salt solutions. By calculating the potential of mean force (free energy as a function of separation) between two benzene molecules to determine the thermodynamics of pair association. To determine the differences between the distribution of anions and cations around a single benzene and the distribution around a benzene pair.

3. To investigate the structure and dynamics of the interface between benzene and water or salt solution. Using simulations to determine the shape and fluctuations of the interface between benzene and water or salt solution. Determining the effects of different salts on these properties including the degree of water and ion penetration into the benzene layer.