Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations

Abstract

Given the ubiquitous nature of protein-DNA interactions, it is important to understand the interaction thermodynamics of individual amino acid sidechains for DNA. One way to assess these preferences is to perform molecular dynamics (MD) simulations. Here we report MD simulations of twenty amino acid sidechain analogs interacting simultaneously with both a 70-base pair double-stranded DNA and with a 70-nucleotide single-stranded DNA. The relative preferences of the amino acid sidechains for dsDNA and ssDNA match well with values deduced from crystallographic analyses of protein-DNA complexes. The estimated apparent free energies of interaction for ssDNA, on the other hand, correlate well with previous simulation values reported for interactions with isolated nucleobases, and with experimental values reported for interactions with guanosine. Comparisons of the interactions with dsDNA and ssDNA indicate that, with the exception of the positively charged sidechains, all types of amino acid sidechain interact more favorably with ssDNA, with intercalation of aromatic and aliphatic sidechains being especially notable. Analysis of the data on a base-by-base basis indicates that positively charged sidechains, as well as sodium ions, preferentially bind to cytosine in ssDNA, and that negatively charged sidechains, and chloride ions, preferentially bind to guanine in ssDNA. These latter observations provide a novel explanation for the lower salt-dependence of DNA duplex stability in GC-rich sequences relative to AT-rich sequences.

RNA‐protein interactions in an unstructured context

“…comes to understanding the basic principles of RNA-IDP interactions in the context of liquid RNA-protein granules characterized by a reduced dielectric constant as compared to bulk water. Importantly, the obtained affinities in water were found to be in an excellent agreement with the results of a subsequent independent analysis by Elcock and coworkers who have performed explicit-solvent MD simulations of long single-and double-stranded DNA molecules in heterogeneous aqueous mixtures of amino acids using a different MD force field [80] (Fig. 3C).…”

“…(C) Andrews et al . nucleobase–amino acid‐binding ΔG scales ( x ‐axis) correlate closely with de Ruiter et al . scales ( y ‐axis) Figure C was reproduced with permission (American Chemical Society) from Ref.…”

“…(C) Andrews et al [80] nucleobase-amino acid-binding DG scales (x-axis) correlate closely with de Ruiter et al scales [81] (y-axis) Figure 3C was reproduced with permission (American Chemical Society) from Ref. [80]. comes to understanding the basic principles of RNA-IDP interactions in the context of liquid RNA-protein granules characterized by a reduced dielectric constant as compared to bulk water.…”

“…Significant progress in understanding nucleobaseamino acid interactions has over the years been made using computational approaches [50, [67][68][69][70][71][72][73][74][75][76][77][78][79][80]. For example, analysis of 3D structures of RNA-or DNA-protein complexes has yielded the relative binding preferences of nucleobases and amino acids together with a geometric and energetic characterization of their interactions [50, 67,68,72,[75][76][77][78][79].…”

“…(B) ADE and URA amino acid-binding free energy scales are up to a constant largely insensitive to local dielectric constant, while those for GUA and CYT strongly depend on it (Pearson Rs given in the inset) [81]. (C) Andrews et al [80] nucleobase-amino acid-binding DG scales (x-axis) correlate closely with de Ruiter et al scales [81] (y-axis) Figure 3C was reproduced with permission (American Chemical Society) from Ref. [80].…”