X-ray diffraction "fingerprinting" of DNA structure in solution for quantitative evaluation of molecular dynamics simulation

Abstract

Solution state x-ray diffraction fingerprinting is demonstrated as a method for experimentally assessing the accuracy of molecular dynamics (MD) simulations. Fourier transforms of coordinate data from MD simulations are used to produce reciprocal space "fingerprints" of atomic pair distance correlations that are characteristic of the ensemble and are the direct numerical analogues of experimental solution x-ray diffraction (SXD). SXD experiments and MD simulations were carried out to test the ability of experiment and simulation to resolve sequence-dependent modifications in helix conformation for B-form DNA. SXD experiments demonstrated that solution-state poly(AT) and poly(A)-poly(T) duplex DNA sequences exist in ensembles close to canonical B-form and B'-form structures, respectively. In contrast, MD simulations analyzed in terms of SXD fingerprints are shown to deviate from experiment, most significantly for poly(A)-poly(T) duplex DNA. Compared with experiment, MD simulation shortcomings were found to include both mismatches in simulated conformer structures and number population within the ensembles. This work demonstrates an experimental approach for quantitatively evaluating MD simulations and other coordinate models to simulate biopolymer structure in solution and suggests opportunities to use solution diffraction data as experimental benchmarks for developing supramolecular force fields optimized for a range of in situ applications.

Fig. 1.

SXD fingerprint patterns calculated from DNA models. (A) SXD fingerprints calculated from canonical duplex models: B-form d(AT)₁₀ (black), B-form d(AT)₅ (red), B′-form d(A)₂₀ (green), and B′-form d(A)₁₀ (blue). (B) SXD fingerprints calculated from a d(A)₁₀ MD B-form conformer using the complete structure (black), the base pair atoms only (red), and sugar–phosphate backbone atoms only (green). The atomic groups are shown as structures 1–3, respectively.

Fig. 2.

SXD patterns from experiment and MD simulation of duplex poly(A)–poly(T) and poly(AT) DNA. (A) Experimental SXD patterns for d(AT)₁₀ (top two traces), d(A)₂₀ (middle two traces), and d(A)₁₀ (bottom two traces) shown pairwise recorded at room temperature (upper trace) and 3°C (lower trace). (B) Ensemble-averaged SXD patterns calculated from MD simulations for d(AT)₁₀ (top trace), d(A)₂₀ (middle trace), and d(A)₁₀ (bottom trace) using simulation conditions AT10.2, A20.2, and A10.3 in Table 2, respectively.

Fig. 3.

Examination of conformer SXD fingerprints within the d(A)₁₀ MD ensemble. (A) SXD patterns calculated for each of the 2,200 conformers generated in simulation A10.1 (black), the ensemble-averaged SXD pattern (red), and a subset-averaged SXD pattern for conformers with B′-form fingerprints (blue), offset for clarity. (B) Overlap of structures representative of the ensemble (green) and B′-form subset (red) averages.

Fig. 4.

A series of MD simulations compared by ensemble-averaged SXD fingerprints. The simulation conditions and parameters are listed in Table 2. Structural parameters tabulated for the MD simulations are listed in Tables 3 and 4.