Ionic Solution: What Goes Right and Wrong with Continuum Solvation Modeling

Solvent-mediated electrostatic interactions were well recognized to be important in the structure and function of molecular systems. Ionic interaction is an important component in electrostatic interactions, especially in highly charged molecules, such as nucleic acids. Here, we focus on the quality of the widely used Poisson–Boltzmann surface area (PBSA) continuum models in modeling ionic interactions by comparing with both explicit solvent simulations and the experiment. In this work, the molality-dependent chemical potentials for sodium chloride (NaCl) electrolyte were first simulated in the SPC/E explicit solvent. Our high-quality simulation agrees well with both the previous study and the experiment. Given the free-energy simulations in SPC/E as the benchmark, we used the same sets of snapshots collected in the SPC/E solvent model for PBSA free-energy calculations in the hope to achieve the maximum consistency between the two solvent models. Our comparative analysis shows that the molality-dependent chemical potentials of NaCl were reproduced well with both linear PB and nonlinear PB methods, although nonlinear PB agrees better with SPC/E and the experiment. Our free-energy simulations also show that the presence of salt increases the hydrophobic effect in a nonlinear fashion, in qualitative agreement with previous theoretical studies of Onsager and Samaras. However, the lack of molality-dependency in the nonelectrostatics continuum models dramatically reduces the overall quality of PBSA methods in modeling salt-dependent energetics. These analyses point to further improvements needed for more robust modeling of solvent-mediated interactions by the continuum solvation frameworks

Comparison of the average RMSDs (per residue) in the (a) target mRNA and (b) guide DNA from the starting native structures of the wild-type and 4 mutants in the 11-bp nucleic acid heteroduplex.

<p>The results are obtained from 1 atm, 310 K NPT simulations (100∼120 ns). The X-axis indicates nucleotide position from the 5′ end of the guide DNA.</p

Time evolution of the wild-type backbone RMSDs and the mismatch mutants from their respective initial “native” structures using longer 15-bp nucleic acid heteroduplex system.

<p>The results are obtained from 1 atm, 310 K NPT simulations for 100∼120 ns. (<b>a</b>). The RMSDs of the DNA-mRNA heteroduplex in Ago complexes (<b>b</b>). The RMSDs of Ago protein in Ago complexes.</p

The dynamic distance of base pairs for the wild-type and 4 mutants in the 11-bp nucleic acid heteroduplex.

<p>Distances are calculated from the C4′–C4′ atoms between the guide DNA strand and the target mRNA strand at the same position. <b>(a)</b>. Distance of the A/T base pair at position 6 <b>(b)</b>. Distance of the U/A base pair at position 7.</p

Time evolution of the backbone RMSDs of wild-type and mismatch mutants from their respective initial “native” structures using the 11-bp nucleic acid heteroduplex system.

<p>The results are obtained from 1 atm, 310 K NPT simulations (100∼120 ns). (<b>a</b>). RMSDs of the DNA-mRNA heteroduplex in Ago complexes (<b>b</b>). RMSDs of Ago protein in Ago complexes.</p

A closer view of the “hinge-like” bending at L1/L2 segment by superposing the final conformation and the starting native structure of the 4-site mutant with 11-bp guide DNA-target RNA duplex.

<p>The nucleic acid and L1/L2 segment in the wild-type are colored orange and green, respectively. The nucleic acid in the 4-site mutant is colored yellow and the L1/L2 segment is colored cyan. The residues that form hydrogen bonds between the guide-target duplex and L1/L2 segment are shown as sticks.</p

Polarizable Multipole-Based Force Field for Aromatic Molecules and Nucleobases

Aromatic molecules with π electrons are commonly involved in chemical and biological recognitions. For example, nucleobases play central roles in DNA/RNA structure and their interactions with proteins. The delocalization of the π electrons is responsible for the high polarizability of aromatic molecules. In this work, the AMOEBA force field has been developed and applied to 5 regular nucleobases and 12 aromatic molecules. The permanent electrostatic energy is expressed as atomic multipole interactions between atom pairs, and many-body polarization is accounted for by mutually induced atomic dipoles. We have systematically investigated aromatic ring stacking and aromatic-water interactions for nucleobases and aromatic molecules, as well as base–base hydrogen-bonding pair interactions, all at various distances and orientations. van der Waals parameters were determined by comparison to the quantum mechanical interaction energy of these dimers and fine-tuned using condensed phase simulation. By comparing to quantum mechanical calculations, we show that the resulting classical potential is able to accurately describe molecular polarizability, molecular vibrational frequency, and dimer interaction energy of these aromatic systems. Condensed phase properties, including hydration free energy, liquid density, and heat of vaporization, are also in good overall agreement with experimental values. The structures of benzene liquid phase and benzene-water solution were also investigated by simulation and compared with experimental and PDB structure derived statistical results

The dynamic distance of base pairs for the wild-type and 4 mutants in the longer 15-bp nucleic acid heteroduplex.

<p>Distances are calculated from the C4′–C4′ atoms between the guide DNA strand and the target mRNA strand at the same position. <b>(a)</b>. Distance of the A/T base pair at position 6 <b>(b)</b>. Distance of the U/A base pair at position 7.</p

Structural comparison and distortion.

<p>Superposition of the final snapshot (colored in blue for the wild-type in the left panel and red for the 4-position mismatch mutant on the right) and the starting native structure (colored in light grey) for both the wild-type and the 4-site mismatch mutant of the 11-bp guide DNA/mRNA heteroduplex after 100+ ns of MD simulation. The backbone is represented as a tube and the rest are shown as plates. The numbers with prime (′) indicate that the nucleic acid belongs to the target strand. Larger distortion in the seed region (position 2 to 8) can be seen clearly on the 4-site mismatch mutant.</p

Structural view of the domain motions in the 4-site mutant Ago complexes with DNA as the guide strand.

<p>Two structures (one colored light grey and the other colored green) are picked from one 100-ns trajectory by principal component analysis and domain motion analysis. The 1^st principal component <b>(a)</b> and the 2^nd principal component <b>(b)</b> are shown here. The Ago protein is represented as cartoon and the four domain names are labeled. The red arrow here indicates the orientation of the domain motions.</p