interactions between solvent and biomolecules

We focused on understanding the interactions between solvent and proteins & nucleic acids, and characterizing the spatial distribution of solvent around biomolecules. It has been long known that both water and counterions, which carry the opposite charges to the biomolecule, accumulate at higher concentrations in the vicinity of the biomolecule’s surface. However, exactly how the distribution takes shape is still elusive. Using computer simulation and liquid state theory, we demonstrated that in addition to the number of ions usually measured in solution X-ray scattering or "ion counting" experiments, the 3-dimensional spatial distribution of solvent could be obtained faithfully. The biomolecule, therefore, could be thought to carry the hydrated and ionic atmosphere around as a molecular "fingerprint". This fingerprint extends quite far away from the biomolecule surface and therefore could facilitate long-ranged molecular recognition. In addition, we have proposed a new method to extract some aspects of the solvent spatial distribution directly from X-ray scattering profiles, expanding the information obtainable from the experiment.

publications

Extracting water and ion distributions from solution x-ray scattering experiments

Hung T. Nguyen, Suzette A. Pabit, Lois Pollack, and David A. Case

J. Chem. Phys., 2016

Abstract HTML

Small-angle X-ray scattering measurements can provide valuable information about the solvent environment around biomolecules, but it can be difficult to extract solvent-specific information from observed intensity profiles. Intensities are proportional to the square of scattering amplitudes, which are complex quantities. Amplitudes in the forward direction are real, and the contribution from a solute of known structure (and from the waters it excludes) can be estimated from theory; hence, the amplitude arising from the solvent environment can be computed by difference. We have found that this “square root subtraction scheme” can be extended to non-zero q values, out to 0.1 Å−1 for the systems considered here, since the phases arising from the solute and from the water environment are nearly identical in this angle range. This allows us to extract aspects of the water and ion distributions (beyond their total numbers), by combining experimental data for the complete system with calculations for the solutes. We use this approach to test molecular dynamics and integral-equation (3D-RISM (three-dimensional reference interaction site model)) models for solvent structure around myoglobin, lysozyme, and a 25 base-pair duplex DNA. Comparisons can be made both in Fourier space and in terms of the distribution of interatomic distances in real space. Generally, computed solvent distributions arising from the MD simulations fit experimental data better than those from 3D-RISM, even though the total small-angle X-ray scattering patterns are very similar; this illustrates the potential power of this sort of analysis to guide the development of computational models.
Accurate small and wide angle x-ray scattering profiles from atomic models of proteins and nucleic acids

Hung T. Nguyen, Suzette A. Pabit, Steve P. Meisburger, Lois Pollack, and David A. Case

J. Chem. Phys., 2014

Abstract HTML Code

A new method is introduced to compute X-ray solution scattering profiles from atomic models of macromolecules. The three-dimensional version of the Reference Interaction Site Model (RISM) from liquid-state statistical mechanics is employed to compute the solvent distribution around the solute, including both water and ions. X-ray scattering profiles are computed from this distribution together with the solute geometry. We describe an efficient procedure for performing this calculation employing a Lebedev grid for the angular averaging. The intensity profiles (which involve no adjustable parameters) match experiment and molecular dynamics simulations up to wide angle for two proteins (lysozyme and myoglobin) in water, as well as the small-angle profiles for a dozen biomolecules taken from the BioIsis.net database. The RISM model is especially well-suited for studies of nucleic acids in salt solution. Use of fiber-diffraction models for the structure of duplex DNA in solution yields close agreement with the observed scattering profiles in both the small and wide angle scattering (SAXS and WAXS) regimes. In addition, computed profiles of anomalous SAXS signals (for Rb+ and Sr2+) emphasize the ionic contribution to scattering and are in reasonable agreement with experiment. In cases where an absolute calibration of the experimental data at q = 0 is available, one can extract a count of the excess number of waters and ions; computed values depend on the closure that is assumed in the solution of the Ornstein–Zernike equations, with results from the Kovalenko–Hirata closure being closest to experiment for the cases studied here.