AI Networking Cookbook: Practical recipes for AI-assisted network automation and development
TL;DR
This study extends HADDOCK to deal with DNA flexibility and is able to successfully predict protein (cid:1) DNA complexes from unbound constituents using non-structural experimental data to drive the docking.
The interface prediction program WHISCY is presented, which combines surface conservation and structural information to predict protein–protein interfaces and demonstrates the potential of using interface predictions to drive protein–protein docking.
Histidine-rich peptides are widely used in affinity-based purification because imidazole donors can coordinate transition-metal ions. To examine how fixed metal-coordination models may alter the predicted DNA-contacting behavior of a histidine hexamer, a fully in silico comparison was performed using metal-free His6 and the tri-metal model complexes [Zn3(His6)]6+, [Ni3(His6)]6+, and [Cu3(His6)]6+ against the canonical B-DNA dodecamer 1BNA [d(CGCGAATTCGCG)]. The formulas denote the neutral-terminal/neutral-imidazole computational representation used for docking and molecular dynamics (MD), rather than a claim concerning the dominant solution-phase species. Molecular docking and MD simulations were used to compare predicted groove localization, recurrent nucleobase-associated contacts, hydrogen-bond patterns, relative docking scores, and trajectory-based structural persistence. Within the examined 1BNA model, metal-free His6 produced a dominant major-groove pose with adenine-associated contacts and a Vina docking score of -8.9 kcal/mol. The tri-metal coordination models produced dominant minor-groove poses with guanine-associated contacts, with relative docking scores of -9.5, -13.5, and -10.8 kcal/mol for the Zn(II), Ni(II), and Cu(II) models, respectively. The Ni(II)- and Cu(II)-containing models also displayed lower RMSD levels than the metal-free complex over the sampled trajectories. These observations are restricted to the defined computational models and the 1BNA sequence; they do not establish experimental binding affinities, universal nucleobase selectivity, or solution-phase metal speciation. The work provides a hypothesis-generating comparison that may guide future experimental investigation of metal-coordinated oligohistidine-DNA interactions.
Double‐stranded DNA molecules are sharply bent into arcs with radii on the order of 10 nanometers in the formation of nucleosomes in biology and when they are looped into minicircles for nanoscale applications. In this Personal Account, we describe our computational efforts over the past several years to understand the structure and dynamics of sharply bent DNA using molecular dynamics simulations. First, using coarse‐grained models of DNA and cationic nanoparticles, we discuss how a small difference in sequence‐dependent DNA flexibility, on the order of 10 nm in persistence length, substantially influences the structure and thermodynamics of DNA–nanoparticle complex formation. Potential of mean force calculations quantify the thermodynamic preference for nanoparticle binding to more flexible DNA, with the free energy difference arising primarily from the sequence‐dependent elastic energy of DNA bending. We then turn to all‐atom simulations of DNA minicircles with approximately 90 base pairs. Sequence‐dependent coupling between DNA bending and its helical twist is identified for specific dinucleotide steps, and the internal dynamics of poloidal rotation and in‐plane circular vibration are characterized on time scales of tens and several nanoseconds, respectively. Finally, we present our recent investigations of mechanically interlocked DNA nanostructures: rotaxanes, in which a DNA minicircle is threaded onto a linear DNA axle, and catenanes, composed of two mutually interlocked DNA minicircles. The effects of torsional stress‐induced shape distortion on the structure and dynamics of these topologically constrained architectures are discussed. Together, these studies illustrate how the interplay of DNA sequence, flexibility, and topology governs the behavior of sharply bent DNA, providing molecular‐level insights for the design of DNA‐based nanoscale devices.
Many functional RNA motifs adopt structures that deviate from the canonical A-form helix and are emerging targets for RNA-directed therapeutics. The microtubule-associated protein tau (MAPT) A-bulge motif (5′-GCAGU/5′-ACGU) is one such motif. Because its structure is stabilized by a delicate balance of local interactions, its accurate modeling remains a major challenge for molecular dynamics (MD) simulations. The experimentally determined nuclear magnetic resonance (NMR) structure of the MAPT A-bulge motif provides a stringent test of whether RNA force fields can accurately reproduce the experimentally observed conformation. Most current AMBER-family RNA force-field models have incorrectly favored a non-native base-triple state of the MAPT A-bulge motif over the experimentally observed stacked state. Structural comparison of the stacked and base-triple conformations revealed that overly favorable NH□–N hydrogen bonds between the bulged adenosine and an adjacent Watson–Crick base pair were the primary source of this imbalance. We developed gHBfix-18Ab, an 18-component hydrogen-bond correction that distinguishes NH and NH□ donors. gHBfix-18Ab was combined with the previously developed OL3CP and NBfix0BPh corrections to generate the composite model gHBfix-18Ab*. This model restored the experimentally observed stacked state as the global minimum in the calculated free-energy profile and improved agreement with NMR-derived distance data for the A-bulge region. Importantly, gHBfix-18Ab* did not produce marked structural destabilization of the cUUCGg tetraloop, a widely used benchmark for RNA force-field validation, suggesting that the refinement preserves the stability of the unrelated RNA motif. These results demonstrate that targeted refinement of hydrogen-bond interactions provides a practical strategy for systematic improvement of RNA force fields toward more accurate modeling of noncanonical RNA motifs. Graphical Summary
Evaluating modern AMBER-based parametrizations across diverse structural motifs, including aptamers, duplexes, and quadruplex-duplex hybrids, provides critical insights for developing next-generation DNA force fields capable of accurately modeling non-native structures and enabling balanced sampling essential for predicting ligand binding in diverse biological contexts.
Interactions between the components of the complex determine the molecular field that ensures complementarity between the contacting structures. In this article, we propose to use AlteQ approach to study DNA polymerase complementarity. The AlteQ approach with good quality describes the experimental electron density which was determined using low temperature high resolution X-ray diffraction. The research methodology was based on constructing electron density 3D maps in the intermolecular contact zone of the complexes, determining the features of the electronic structure, and then establishing the complementarity of the structures to their environment. DNA polymerase complexes with G•C and A•T base pairs were studied. As a result, the zones that determine the complementary field of the complex in terms of electron density were established. It has been established that the environment actively participates in intermolecular interactions, influencing the complementary field. Characteristics that describe the set of intermolecular interactions in the complexes were determined and can be used to assess the binding quality of bases.
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