Efficient and Accurate Potential Energy Surfaces of Puckering in Sugar-Modified Nucleosides

Abstract

Puckering of the sugar unit in nucleosides and nucleotides is an important structural aspect that directly influences the helical structure of nucleic acids. The preference for specific puckering modes in nucleic acids can be analyzed via in silico conformational analysis, but the large amount of conformations and the accuracy of the analysis leads to an extensive amount of computational time. In this paper, we show that the combination of geometry optimizations with the HF-3c method with single point energies at the RI-MP2 level results in accurate results for the puckering potential energy surface (PES) of DNA and RNA nucleosides while significantly reducing the necessary computational time. Applying this method to a series of known xeno nucleic acids (XNAs) allowed us to rapidly explore the puckering PES of each of the respective nucleosides and to explore the puckering PES of six-membered modified XNA (HNA and β-homo-DNA) for the first time.

Fast and Accurate Quantum Mechanical Modeling of Large Molecular Systems Using Small Basis Set Hartree–Fock Methods Corrected with Atom-Centered Potentials

“…The training set (Table ) comprises noncovalent interaction energies, molecular conformational energies, and molecular deformation energies. This choice of training set properties is justified by the potential target applications of small basis set HF-based methods, namely, fast geometry optimizations and noncovalent interaction strengths in large systems as well as high-throughput screening of conformers in combination with conformer search techniques. − These applications are useful, for instance, when performing exhaustive conformational searches of macrocyclic drugs − and other pharmaceutical candidates and studying biochemical processes like protein folding − and puckering of nucleotides. , …”

“…88−90 These applications are useful, for instance, when performing exhaustive conformational searches of macrocyclic drugs 91−96 and other pharmaceutical candidates 97 and studying biochemical processes like protein folding 98−100 and puckering of nucleotides. 101,102 A successful method for noncovalent interactions must be able to accurately describe diverse noncovalent interaction motifs, which means that the training set must contain some of this diversity. For instance, the importance of π−π interactions is well known in medicinal chemistry, 103 structural biology, 104,105 and organic electronics.…”

From polymerase engineering to semi-synthetic life: artificial expansion of the central dogma

“…harbor six-membered rings instead of five-membered rings in their backbones, and retain the ability to hybridize with complementary strands of DNA or RNA 54,55 . The sugar rings of different sugar-modified nucleic acids possess varied pucker conformations, which are closely related with the overall helical structures and stabilities of the nucleic acid duplexes [56][57][58] . Replacement of the entire sugar-phosphate backbone of DNA with a peptide backbone produces peptide nucleic acid (PNA), which can hybridize with DNA or RNA with enhanced melting temperatures, and is highly resistant to nuclease degradation 59,60 .…”

Structural, Electronic, Reactivity, and Conformational Features of 2,5,5-Trimethyl-1,3,2-diheterophosphinane-2-sulfide, and Its Derivatives: DFT, MEP, and NBO Calculations

“…conformations) for anti-bonding orbitals is antiperiplanar (ap) (Figure 3). Several factors influence stereoelectronic effects, such as the difference in energy between the overlapping donor-acceptor orbitals and their presence in a synclinal arrangement (sc) [43,44]. As a result, the σ X-C6 →σ* P-C8 and σ X-C6 →σ* P-S electron delocalization, as depicted in Figure 3, cannot have high stability energy.…”