The energy-spectrum of bicompatible sequences

Fenix W. Huang; Christopher L. Barrett; Christian M. Reidys

Home/Archive/arXiv

arXiv · 1910.00190

The energy-spectrum of bicompatible sequences

Fenix W. Huang·Christopher L. Barrett·Christian M. Reidys

View original source ↗Read source document ↗Export metadata ↓

Abstract

Background: Genotype-phenotype maps provide a meaningful filtration of sequence space and RNA secondary structures are particular such phenotypes. Compatible sequences i.e.~sequences that satisfy the base pairing constraints of a given RNA structure play an important role in the context of neutral networks and inverse folding. Sequences satisfying the constraints of two structures simultaneously are called bicompatible and phenotypic change, induced by erroneously replicating populations of RNA sequences, is closely connected to bicompatibility. Furthermore, bicompatible sequences are relevant for riboswitch sequences, beacons of evolution, realizing two distinct phenotypes. Results: We present a full loop energy model Boltzmann sampler of bicompatible sequences for pairs of structures. The novel dynamic programming algorithm is based on a topological framework encapsulating the relations between loops. We utilize our sequence sampler to study the energy spectra and density of bicompatible sequences, the rankings of the structures and key properties for evolutionary transitions. Conclusion: Our analysis of riboswitch sequences shows that key properties of bicompatible sequences depend on the particular pair of structures. While there always exist bicompatible sequences for random structure pairs, they are less suited to facilitate transitions. We show that native riboswitch sequences exhibit a distinct signature with regards to the ranking of their two phenotypes relative to the minimum free energy, suggesting a new criterion for identifying native sequences and sequences subjected to evolutionary pressure.

Explore related subjects

q-bio.BM math.CO

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Fenix W. Huang, Christopher L. Barrett, Christian M. Reidys. 2019-10-01. The energy-spectrum of bicompatible sequences. https://arxiv.org/abs/1910.00190

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related papers

arXiv2026

Synthesizing State-of-the-Art Structure Predictions from Soup of Co-folding Models

Co-folding models have advanced rapidly, yet no single model consistently performs best across all biomolecular complexes. This raises the question of whether independently trained co-folding models encode complementary information that can be transferred across co-folding models. We introduce SoupFold, which improves co-folding predictions by learning simple mappings between the representation spaces of co-folding models. At inference time, SoupFold transfers and incorporates representations from other co-folding models to update the representation used for structure prediction. Importantly, this does not re-train the co-folding models. We evaluate SoupFold on protein-protein and protein-ligand prediction tasks of FoldBench using AlphaFold3, Protenix, ESMFold2, and OpenDDE. By combining their representations, SoupFold achieves state-of-the-art performance on both protein-protein and protein-ligand structure prediction, showing that independently trained co-folding models encode complementary information that can be effectively transferred across models.

q-bio.BM↗

arXiv2026

Sequence-Informed Geometric Evaluation of RNA 3D Structures

Computational RNA structure pipelines generate many candidate conformations for the same sequence. Reliable evaluation therefore requires more than recognising plausible geometry, it requires determining whether that geometry is compatible with the sequence. We introduce SIRGE, a sequence-informed geometric evaluator that conditions structural representations on nucleotide embeddings from a pretrained RNA language model. Early results show that SIRGE outperforms established evaluators in Kendall--$τ$ alignment, Top-1 selection, and Top-3 ranking. Controlled comparisons further show that sequence conditioning corrects errors made by an otherwise matched geometric model and improves target-level rank structure. These findings provide initial evidence that pretrained sequence representations supply ranking information that complements geometric reasoning.

q-bio.BM↗

arXiv2026

PocketVE: Stable and Property-Guided Structure-Based Drug Design with Variance-Exploding Diffusion

Protein-conditioned 3D molecule generation is a central challenge in structure-based drug design, requiring a balance between pocket compatibility, molecular properties, and physical geometry. We propose \textbf{PocketVE}, a protein-pocket-conditioned variance-exploding (VE) diffusion framework that couples stable coordinate denoising with inference-time property guidance. Specifically, PocketVE combines an EDM-style training and sampling setup for 3D denoising, classifier-free guidance for multi-property steering without external property classifiers, and adaptive protein perturbation as a training-time pocket regularizer. Evaluated on CrossDocked2020 under the GenBench3D protocol, PocketVE improves Valid$_{3\text{D}}$ from 58.6 to 80.6 and reduces strain energy from 457.4 to 127.9 relative to its TAGMol architectural baseline, while retaining competitive docking and molecular-property scores under moderate guidance. A guidance-scale study shows that moderate guidance gives a favorable balance between target-related objectives and geometric quality, whereas stronger guidance can degrade geometry and distributional fidelity. Pocket-permutation and PoseCheck diagnostics further support pocket-specific spatial compatibility with reduced steric conflicts. Overall, the results suggest that geometric stability and inference-time property guidance should be considered as coupled design objectives.

q-bio.BM↗