AlphaFold2 some protein folding principles.

AlphaFold2 (AF2) has revolutionized protein structure prediction. However, a common confusion lies in equating the problem with the . The former provides a static structure, while the latter explains the dynamic folding pathway to that structure.

Revolutionizing Peptide-Based Drug Discovery: Advances in the Post-AlphaFold Era.

Peptide-based drugs offer high specificity, potency, and selectivity. However, their inherent flexibility and differences in conformational preferences between their free and bound states create unique challenges that have hindered progress in effective drug discovery pipelines. The emergence of AlphaFold (AF) and Artificial Intelligence (AI) presents new opportunities for enhancing peptide-based drug discovery.

Modelling peptide-protein complexes: docking, simulations and machine learning.

Peptides mediate up to 40% of protein interactions, their high specificity and ability to bind in places where small molecules cannot make them potential drug candidates. However, predicting peptide-protein complexes remains more challenging than protein-protein or protein-small molecule interactions, in part due to the high flexibility peptides have. In this review, we look at the advances in docking, molecular simulations and machine learning to tackle problems related to peptides such as predicting structures, binding affinities or even kinetics.

Engineering highly thermostable Cas12b via de novo structural analyses for one-pot detection of nucleic acids.

CRISPR-Cas-based diagnostics have the potential to elevate nucleic acid detection. CRISPR-Cas systems can be combined with a pre-amplification step in a one-pot reaction to simplify the workflow and reduce carryover contamination. Here, we report an engineered Cas12b with improved thermostability that falls within the optimal temperature range (60°C-65°C) of reverse transcription-loop-mediated isothermal amplification (RT-LAMP).

CryoFold 2.0: Cryo-EM Structure Determination with MELD.

Cryo-electron microscopy data are becoming more prevalent and accessible at higher resolution levels, leading to the development of new computational tools to determine the atomic structure of macromolecules. However, while existing tools adapted from X-ray crystallography are suitable for the highest-resolution maps, new tools are needed for lower-resolution levels and to account for map heterogeneity. In this article, we introduce CryoFold 2.

Ranking Peptide Binders by Affinity with AlphaFold.

AlphaFold has revolutionized structural biology by predicting highly accurate structures of proteins and their complexes with peptides and other proteins. However, for protein-peptide systems, we are also interested in identifying the highest affinity binder among a set of candidate peptides. We present a novel competitive binding assay using AlphaFold to predict structures of the receptor in the presence of two peptides.

Towards rational computational peptide design.

Peptides are prevalent in biology, mediating as many as 40% of protein-protein interactions, and involved in other cellular functions such as transport and signaling. Their ability to bind with high specificity make them promising therapeutical agents with intermediate properties between small molecules and large biologics. Beyond their biological role, peptides can be programmed to self-assembly, and they are already being used for functions as diverse as oligonuclotide delivery, tissue regeneration or as drugs.

Deciphering the Folding Mechanism of Proteins G and L and Their Mutants.

Much of our understanding of folding mechanisms comes from interpretations of experimental ϕ and ψ value analysis, relating the differences in stability of the transition state ensemble (TSE) and folded state. We introduce a unified approach combining simulations and Bayesian inference to provide atomistic detail for the folding mechanism of proteins G and L and their mutants. Proteins G and L fold to similar topologies despite low sequence similarity, but differ in their folding pathways.

Improvement of Unilateral Breast Hypoplasia With Oral Spironolactone in a Patient With Becker Nevus Syndrome.

Becker nevus (BN) is a benign cutaneous smooth muscle hamartoma that presents with a hyperpigmented patch or plaque with or without hypertrichosis.1 BN may be associated with ipsilateral breast hypoplasia or other musculoskeletal abnormalities, an association which has been termed Becker nevus syndrome (BNS).

Improving the analysis of biological ensembles through extended similarity measures.

We present new algorithms to classify structural ensembles of macromolecules based on the recently proposed extended similarity measures. Molecular dynamics provides a wealth of structural information on systems of biological interest. As computer power increases, we capture larger ensembles and larger conformational transitions between states.

An integrative approach identifies dysregulated long non-coding RNAs as microRNA decoys during nevus to melanoma transformation.

Mounting evidence supports a role for dysregulated long non-coding RNAs (lncRNA) in the development of many cancers. A recently discovered function of lncRNAs is to act as microRNA (miR) decoys or competing endogenous RNAs, which sequester specific miRs and relieve negative regulation of mRNA expression by miRs. Although a large number of non-coding RNAs are thought to function as competing endogenous RNAs, miR-sequestering lncRNAs involved in nevus to melanoma transformation remain largely unknown.

The benefit of poor mixing: kinetics of coacervation.

Complex coacervation has become a prominent area of research in the fields of food science, personal care, drug stabilization, and more. However, little has been reported on the kinetics of assembly of coacervation itself. Here, we describe a simple, low-cost way of looking at the kinetics of coacervation by creating poorly mixed samples.

Melanoma Ex Blue Nevus With GNA11 Mutation and BAP1 Loss: Case Report and Review of the Literature.

Cutaneous melanomas may demonstrate a variety of histopathological features and genetic abnormalities. Melanomas that arise in the setting of blue nevi, also known as "malignant blue nevus" or melanoma ex blue nevus (MBN), share a similar histopathological and mutational profile with uveal melanoma. Most uveal melanomas show characteristic GNA11 or GNAQ mutations; additional BAP1 mutation or loss is associated with the highest risk of metastasis and worst prognosis.

Designing Electrostatic Interactions via Polyelectrolyte Monomer Sequence.

Charged polymers are ubiquitous in biological systems because electrostatic interactions can drive complicated structure formation and respond to environmental parameters such as ionic strength and pH. In these systems, function emerges from sophisticated molecular design; for example, intrinsically disordered proteins leverage specific sequences of monomeric charges to control the formation and function of intracellular compartments known as membraneless organelles. The role of a charged monomer sequence in dictating the strength of electrostatic interactions remains poorly understood despite extensive evidence that sequence is a powerful tool biology uses to tune soft materials.

Sequence and entropy-based control of complex coacervates.

Biomacromolecules rely on the precise placement of monomers to encode information for structure, function, and physiology. Efforts to emulate this complexity via the synthetic control of chemical sequence in polymers are finding success; however, there is little understanding of how to translate monomer sequence to physical material properties. Here we establish design rules for implementing this sequence-control in materials known as complex coacervates.

Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation.

Background: Melanoma is a heterogeneous malignancy. We set out to identify the molecular underpinnings of high-risk melanomas, those that are likely to progress rapidly, metastasize, and result in poor outcomes.

Methods: We examined transcriptome changes from benign states to early-, intermediate-, and late-stage tumors using a set of 78 treatment-naive melanocytic tumors consisting of primary melanomas of the skin and benign melanocytic lesions.

Populus euphratica HSF binds the promoter of WRKY1 to enhance salt tolerance.

Poplar species increase expressions of transcription factors to deal with salt environments. We assessed the salt-induced transcriptional responses of heat-shock transcription factor (HSF) and WRKY1 in Populus euphratica, and their roles in salt tolerance. High NaCl (200mM) induced PeHSF and PeWRKY1 expressions in P.

Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.

Most B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions REs from normal GC B cells and commandeers enhancers from other lineages.

Differentially expressed microRNAs in chondrocytes from distinct regions of developing human cartilage.

There is compelling in vivo evidence from reports on human genetic mutations and transgenic mice that some microRNAs (miRNAs) play an important functional role in regulating skeletal development and growth. A number of published in vitro studies also point toward a role for miRNAs in controlling chondrocyte gene expression and differentiation. However, information on miRNAs that may regulate a specific phase of chondrocyte differentiation (i.