DFT study of polymorphism of the DNA double helix at the level of dinucleoside monophosphates

Abstract

ABSTRACT:We apply DFT calculations to deoxydinucleoside monophosphates (dDMPs) which represent minimal fragments of the DNA chain to study the molecular basis of stability of the DNA duplex, the origin of its polymorphism and conformational heterogeneity. In this work, we continue our previous studies of dDMPs where we detected internal energy minima corresponding to the ''classical'' B conformation (BI-form), which is the dominant form in the crystals of oligonucleotide duplexes. We obtained BI local energy minima for all existing base sequences of dDMPs. In the present study, we extend our analysis to other families of DNA conformations, successfully identifying A, BI, and BII energy minima for all dDMP sequences. These conformations demonstrate distinct differences in sugar ring puckering, but similar sequence-dependent base arrangements. Internal energies of BI and BII conformers are close to each other for nearly all the base sequences. The dGpdG, dTpdG, and dCpdA dDMPs slightly favor the BII conformation, which agrees with these sequences being more frequently experimentally encountered in the BII form. We have found BII-like structures of dDMPs for the base sequences both existing in crystals in BII conformation and those not yet encountered in crystals till now. On the other hand, we failed to obtain dDMP energy minima corresponding to the Z family of DNA conformations, thus giving us the ground to conclude that these conformations are stabilized in both crystals and solutions by external factors, presumably by interactions with various components of the media. Overall the accumulated computational data demonstrate that the A, BI, and BII families of DNA conformations originate from the corresponding local energy minimum conformations of dDMPs, thus determining structural stability of a single DNA strand during the processes of unwinding and rewinding of DNA.

The role of molecular structure of sugar‐phosphate backbone and nucleic acid bases in the formation of single‐stranded and double‐stranded DNA structures

“…Our subsequent computational studies extended to all 16 possible nucleoside sequences of dDMPs and to four families of WC duplexes (BI, BII, AI, and AII) reinforced the above conclusion. Specifically, the regions of sugar‐phosphate backbone torsions and sugar puckering characteristics obtained in geometry optimized dDMPs in all 16 nucleotide sequences reproduced the range of the values that uniquely identifies the corresponding DNA duplex families in crystals.…”

“…Thus, we demonstrated that general characteristics of three‐dimensional structures of WC duplexes and their sequence dependence are predefined in local energy minima of dDMPs, i.e., in the minimal fragments of DNA single strand. Based on analysis of these data we arrived to the conclusion about important role of sugar‐phosphate backbone in the formation and sequence dependence properties of DNA duplexes …”

“…The purpose of this work is to uncover the additional previously unknown details on the active role of chemically monotonous sugar‐phosphate backbone in specific sequence dependence of dDMPs, and to study its role in 3D double helix structure formation in general. We are going to extend our previous studies to clarify the nucleic base structure contribution in sequence dependence by performing computations of dDMPs starting from previously optimized conformations for other sequences, as well as to perform density functional theory (DFT) computations of various configurations of the backbone alone without bases. Considering the possibility that dDMPs could be too small model for DNA to derive general conclusions about the helix, we are also going to briefly mention preliminary results obtained for more extended DNA fragments, namely complexes of complementary dDMPs, cdDMPs, and deoxytrinucleoside diphosphates, dTDPs.…”

Developing a computational model that accurately reproduces the structural features of a dinucleoside monophosphate unit within B-DNA

“…4b and 3c), where the angle between the nucleobase planes (j) ranges from 371 to 571 (Table 1). Generally, these tilted arrangements are accompanied by pyramidalization of the amino group at C2 in G, which has been noted in previous structural studies of dinucleoside monophosphates [28][29][30] and leads to an out-ofplane N-HÁÁÁO hydrogen bond with O4 0 of the 3 0 -deoxyribose sugar and/or the O4 carbonyl group of the pyrimidine.…”

“…86 The j angle has been previously used to quantify base-base orientations in DNA [28][29][30] and combines the values of tilt and roll commonly used to describe nucleic acid structure. 72 To further aid structural characterization, we developed a categorization scheme for the optimized structures, which we classify as:…”