C–B–A Test of DNA Force Fields

Abstract

The DNA duplex may be locally strongly bent in complexes with proteins, for example, with polymerases or in a nucleosome. At such bends, the DNA helix is locally in the noncanonical forms A (with a narrow major groove and a large amount of north sugars) or C (with a narrow minor groove and a large share of BII phosphates). To model the formation of such complexes by molecular dynamics methods, the force field is required to reproduce these conformational transitions for a naked DNA. We analyzed the available experimental data on the B–C and B–A transitions under the conditions easily implemented in modeling: in an aqueous NaCl solution. We selected six DNA duplexes which conformations at different salt concentrations are known reliably enough. At low salt concentrations, poly(GC) and poly(A) are in the B-form, classical and slightly shifted to the A-form, respectively. The duplexes ATAT and GGTATACC have a strong and salt concentration dependent bias toward the A-form. The polymers poly(AC) and poly(G) take the C- and A-forms, respectively, at high salt concentrations. The reproduction of the behavior of these oligomers can serve as a test for the balance of interactions between the base stacking and the conformational flexibility of the sugar–phosphate backbone in a DNA force field. We tested the AMBER bsc1 and CHARMM36 force fields and their hybrids, and we failed to reproduce the experiment. In all the force fields, the salt concentration dependence is very weak. The known B-philicity of the AMBER force field proved to result from the B-philicity of its excessively strong base stacking. In the CHARMM force field, the B-form is a result of a fragile balance between the A-philic base stacking (especially for G:C pairs) and the C-philic backbone. Finally, we analyzed some recent simulations of the LacI-, SOX-4-, and Sac7d-DNA complex formation in the framework of the AMBER force field.

Assessment of A- to B- DNA Transitions Utilizing the Drude Polarizable Force Field

“…Finally, looking at the helical properties and dihedral angles showed no difference between the duplex properties ( Supporting Information Figures S35 and S36 ). While previous work has suggested a B-DNA to A-DNA transitions in salt as high as 5 M, 24 , 26 other experimental and theoretical works has suggest A-DNA characteristics can be seen at lower salt concentrations. 55 , 56 Utilizing the resources available on the Charmm-GUI Web site, a max salt concentration was reached at 3M.…”

“…With Charmm, root-mean squared deviations support a structure more akin to A-DNA than B-DNA in 75% EtOH with the Charmm 27_2b force field; however, detailed structural characterization was not provided . Recently, a combination of Charmm and Amber parameters was successfully utilized to induce structural transitions in a high-salt solution . However, when used independently, neither Charmm36 nor Amber additive force fields were able to facilitate B- to A- transitions in low water activity environments.…”

“… 25 Recently, a combination of Charmm and Amber parameters was successfully utilized to induce structural transitions in a high-salt solution. 26 However, when used independently, neither Charmm36 nor Amber additive force fields were able to facilitate B- to A- transitions in low water activity environments. Using a polarizable force field, which is a more accurate representation of the electrostatic environment that drives these transitions, could be a solution to this challenge.…”

Computational Modeling of DNA 3D Structures: From Dynamics and Mechanics to Folding

“…MD simulations have been effective in accurately probing the atomic motions and structural dynamics of DNAs [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ], enabling us to understand the DNA functions. To address the question of how long an MD simulation of a B-DNA helix needs to be to sample the dominant structural and dynamical features, Galindo-Murillo et al presented an extensive analysis using multiple μs-length MD simulations of a dsDNA (d(GCACGAACGAACGAACGC)) with Amber 14 and a ff99SB parmbsc0 or CHARMM C36 force field on multiple computer architectures (including Anton, CPU, and GPU).…”

Near‐IR‐Absorbing Bis‐Donor Functionalized Aza‐BODIPY Derivatives: Synthesis and Photophysical Study by Using Transient Optical Spectroscopy

“…Aza‐BDP dyes possess favorable spectroscopic properties, including high molar absorption coefficients, intense NIR absorption and excellent photostability [26–36] . Aza‐BDPs have been used for various applications, such as solar cells, photosensitizers, chemosensors and bioimaging [37–46] . Our group is involved in the design and synthesis of donor‐acceptor (D‐A) architectures with NIR absorption for solution processed bulk heterojunction organic solar cells (BHJ‐OSCs) [47–51] …”