Searcharxiv⌕ Search
Home/Archive/arXiv

arXiv · 2310.15779

Analysis of proteins in the light of mutations

Jorge A. Vila
View original source ↗Read source document ↗Export metadata ↓

Abstract

Proteins have evolved through mutations, amino acid substitutions, since life appeared on Earth, some 109 years ago. The study of these phenomena has been of particular significance because of their impact on protein stability, function, and structure. Three of the most recent findings in these areas deserve to be highlighted. First, an innovative method has made it feasible to massively determine the impact of mutations on protein stability. Second, a theoretical analysis showed how mutations impact the evolution of protein folding rates. Lastly, it has been shown that native-state structural changes brought on by mutations can be explained in detail by the amide hydrogen exchange protection factors. This study offers a new perspective on how those findings can be used to analyze proteins in the light of mutations. The preliminary results indicate that: (i) mutations can be viewed as sensitive probes to identify "typos" in the amino-acid sequence and also to assess the resistance of naturally occurring proteins to unwanted sequence alterations; (ii) the presence of "typos" in the amino acid sequence, rather than being an evolutionary obstacle, could promote faster evolvability and, in turn, increase the likelihood of higher protein stability; (iii) the mutation site is far more important than the substituted amino acid in terms of the protein's marginal stability changes, and (iv) the protein evolution unpredictability at the molecular level by mutations exists even in the absence of epistasis effects. Finally, the study results support the Darwinian concept of evolution as "descent with modification" by demonstrating that some regions of any protein sequence are susceptible to mutations while others are not.

Explore related subjects

q-bio.BM

Keep this discovery

BibTeXRIS

Jorge A. Vila. 2023-10-24. Analysis of proteins in the light of mutations. https://arxiv.org/abs/2310.15779

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

KEEP EXPLORING

Related papers

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--$\tau$ 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↗
arXiv2026

Predicting directional flexibility in proteins

Predicting protein dynamics is a long-standing problem in computational structural biology. Often, protein function critically depends on local directed motions, such as hinge movements, catalytic loop rearrangements and domain reorientations, which can be characterized by directional flexibility and correlated structural motions of the protein backbone. While Molecular Dynamics (MD) simulations provide an established but often prohibitively expensive approach, recent deep generative models aim to reduce this cost by directly predicting conformational ensembles, emulating MD. However, due to their large size and the need to generate several states until the derived dynamical properties converge, these models remain expensive. In this work, we propose BackFlip-2: a fast SE(3)-equivariant graph neural network trained to directly predict dynamical descriptors, such as directional backbone flexibility and pairwise dynamic correlations, from an equilibrium structure. In a series of experiments, we show that our model matches the accuracy of substantially larger ensemble generation models while being orders of magnitude faster, and demonstrate that the proposed equivariant architecture is especially well-suited for capturing anisotropic motions in proteins. BackFlip-2 model weights, training and inference code are available at https://github.com/graeter-group/backflip.

q-bio.BM↗