The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA

A multivariate analysis of the backbone and sugar torsion angles of dinucleotide fragments was used to construct a 3D principal conformational subspace (PCS) of DNA duplex crystal structures. The potential energy surface (PES) within the PCS was mapped for a single-strand dinucleotide model using an empirical energy function. The low energy regions of the surface encompass known DNA forms and also identify previously unclassified conformers. The physical determinants of the conformational landscape are found to be predominantly steric interactions within the dinucleotide backbone, with medium-dependent backbone-base electrostatic interactions serving to tune the relative stability of the different local energy minima. The fidelity of the PES to duplex DNA properties is validated through a correspondence to the conformational distribution of duplex DNA crystal structures and the reproduction of observed sequence specific propensities for the formation of A-form DNA. The utility of the PES is demonstrated through its succinct and accurate description of complex conformational processes in simulations of duplex DNA. The study suggests that stereochemical considerations of the nucleic acid backbone play a role in determining conformational preferences of DNA which is analogous to the role of local steric interactions in determining polypeptide secondary structure

Polyomaviridae Assembly Polymorphism from an Energy Landscape Perspective

Polyomaviridae assemble in vitro into different aggregates depending on experimental conditions. We use an energy landscape approach using empirical energy calculations to quantify how the formation of these different aggregates depends on pH, the presence of bound calcium ions and disulfide linkages. Computations are carried out for SV40, a member of the Polyomaviridae family and are based on the binding free energy landscape of three distinct trimers of pentamers that correspond to the different bonding configurations between the capsid proteins observed in its crystal structure. Our computational analysis shows that the energetics of one of these environments is pivotal for the polymorphic assembly behaviour of SV40, whilst the binding energy landscapes of the other two environments are broadly funnel-shaped and thus contribute little to the formation of particles other than virus-like particles (VLP). We have quantified how the existence of bound calcium ions in the absence of disulfide linkages enhances the binding free energies of all three environments and hence, favours the assembly of VLPs. Moreover, estimation of the relative binding free energies of the three environments at pH 5 and pH 8 reveals that they are destabilized at pH 5 relative to pH 8. The extent of this destabilization is dependent on the presence of disulfide linkages and bound calcium ions and accounts for the experimentally observed polymorphic behaviour of VP1 proteins at pH 5. Interestingly, concurrent existence of bound calcium ions and disulfide linkages is found to be destabilizing and thus may disrupt the assembly of VLPs at pH 8

Distributions of the sugar psuedorotation angles P1, P2 and backbone torsion pairs; (ɛ−γ), (α,γ) in each energy valley

<p><b>Copyright information:</b></p><p>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"</p><p>Nucleic Acids Research 2005;33(18):5749-5762.</p><p>Published online 7 Oct 2005</p><p>PMCID:PMC1253833.</p><p>© The Author 2005. Published by Oxford University Press. All rights reserved</p> P1 and α are shown in green while P2 and γ are in red. Positions of corresponding minima are indicated by dotted lines. Densities are based on a GC subspace PES

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

10.4161/15384101.2014.989043Cell Cycle142179-18