RNA binding and coacervation promote preservation of peptide form and function across the heterochiral-homochiral divide.

Recent evidence suggests that peptide-RNA coacervates may have buffered the emergence of folded domains from flexible peptides. As primitive peptides were likely composed of both L- and D-amino acids, we hypothesized that coacervates may have also supported the emergence of chiral control. To test this hypothesis, we compared the coacervation propensities of an isotactic (homochiral) peptide and a syndiotactic (alternating chirality) peptide, both with an identical sequence derived from the ancient helix-hairpin-helix (HhH) motif.

Intersegment Transfer and the Dynamical Architecture of Fis Protein-DNA Multimer Complexes.

Gene regulation often entails a cooperative dynamic interplay among several protein molecules and several distinct DNA segments. Intersegment transfer of the Fis protein stimulates DNA inversion during DNA recombination. Individual DNA segments have been found to facilitate the dissociation of Fis proteins already bound to DNA and also allow for the transfer of the Fis between segments.

Ion-mediated effects of glycosylation on the disordered mucin domain: Insights from coarse-grained simulations.

Mucins are essential glycoproteins that form the backbone of mucus, a hydrogel protecting epithelial surfaces throughout the body. Their biophysical properties are governed by the densely glycosylated and highly disordered proline-threonine-serine (PTS) mucin domain, which becomes negatively charged by the addition of terminal sialic acid and sulfate groups to its glycans. The properties of mucins are further modulated by their interactions with cations, particularly sodium and calcium, which influence mucus expansion and viscoelasticity.

Competition between Nucleic Acids and Intrinsically Disordered Regions within Proteins.

ConspectusIntrinsically disordered regions (IDRs) are important components of protein functionality, with their charge distribution serving as a key factor in determining their roles. Notably, many proteins possess IDRs that are highly negatively charged, characterized by sequences that are rich in aspartate (D) or glutamate (E) residues. Bioinformatic analyses indicate that negatively charged, low-complexity IDRs are significantly more common than their positively charged counterparts rich in arginine (R) or lysine (K).

Theoretical Understanding of Target Search Dynamics in Horizontal Gene Transfer in Bacteria.

Horizontal gene transfer (HGT) is a fundamental process of increasing genetic diversity in microbial species. It allows bacterial cells to acquire new beneficial traits quickly by incorporating new genetic material into existing genomes. Despite the critical importance of HGT phenomena, the underlying molecular mechanisms are still poorly understood.

Inhibition of tau aggregation by the CCT3 and CCT7 apical domains.

The eukaryotic chaperonin containing t-complex polypeptide 1 (CCT/TRiC) is a molecular chaperone that assists protein folding in an ATP-driven manner. It consists of two stacked identical rings that are each made up of eight distinct subunits. Here, we show that the apical domains of subunits CCT3 and CCT7 from humans are strong inhibitors of tau aggregation, which is associated with several neurological disorders such as Alzheimer's and Parkinson's diseases.

Functional Ambidexterity of an Ancient Nucleic Acid-Binding Domain.

The helix-hairpin-helix (HhH) motif is an ancient and ubiquitous nucleic acid-binding element that has emerged as a model system for studying the evolution of dsDNA-binding domains from simple peptides that phase separate with RNA. We analyzed the entire putative evolutionary trajectory of the HhH motif - from a flexible peptide to a folded domain - for functional robustness to total chiral inversion. Against expectations, functional "ambidexterity" was observed for both the phase separation of HhH peptides with RNA and binding of the duplicated (HhH)-Fold to dsDNA.

A pH-Dependent Coarse-Grained Model for Disordered Proteins: Histidine Interactions Modulate Conformational Ensembles.

Histidine (His) presents a unique challenge for modeling disordered protein conformations, as it is versatile and occurs in both the neutral (His) and positively charged (His) states. These His charge states, which are enabled by its imidazole side chain, influence the electrostatic and short-range interactions of His residues, which potentially engage in cation-π, π-π, and charge-charge interactions. Existing coarse-grained (CG) models often simplify His representation by assigning it an average charge, thereby neglecting these potential short-range interactions.

Aromatic Residues in Proteins: Re-Evaluating the Geometry and Energetics of π-π, Cation-π, and CH-π Interactions.

Aromatic residues can participate in various biomolecular interactions, such as π-π, cation-π, and CH-π interactions, which are essential for protein structure and function. Here, we re-evaluate the geometry and energetics of these interactions using quantum mechanical (QM) calculations, focusing on pairwise interactions involving the aromatic amino acids Phe, Tyr, and Trp and the cationic amino acids Arg and Lys. Our findings reveal that π-π interactions, while energetically favorable, are less abundant in structured proteins than commonly assumed and are often overshadowed by previously underappreciated, yet prevalent, CH-π interactions.

The structure of the Lujo virus spike complex.

Lujo virus (LUJV) is a human pathogen that was the cause of a deadly hemorrhagic fever outbreak in Africa. LUJV is a divergent member of the Arenaviridae with some similarities to both the "Old World" and "New World" serogroups, but it uses a cell-entry receptor, neuropilin-2 (NRP2), that is distinct from the receptors of OW and NW viruses. Though the receptor binding domain of LUJV has been characterized structurally, the overall organization of the trimeric spike complex and how NRP2 is recognized in this context were unknown.

Sound-mediated nucleation and growth of amyloid fibrils.

Mechanical energy, specifically in the form of ultrasound, can induce pressure variations and temperature fluctuations when applied to an aqueous media. These conditions can both positively and negatively affect protein complexes, consequently altering their stability, folding patterns, and self-assembling behavior. Despite much scientific progress, our current understanding of the effects of ultrasound on the self-assembly of amyloidogenic proteins remains limited.

Histidine in Proteins: pH-Dependent Interplay between π-π, Cation-π, and CH-π Interactions.

Histidine (His) stands out as the most versatile natural amino acid due to its side chain's facile propensity to protonate at physiological pH, leading to a transition from aromatic to cationic characteristics and thereby enabling diverse biomolecular interactions. In this study, our objective was to quantify the energetics and geometries of pairwise interactions involving His at varying pH levels. Through quantum chemical calculations, we discovered that His exhibits robust participation in both π-π and cation-π interactions, underscoring its ability to adopt a π or cationic nature, akin to other common residues.

Partial wrapping of single-stranded DNA by replication protein A and modulation through phosphorylation.

Single-stranded DNA (ssDNA) intermediates which emerge during DNA metabolic processes are shielded by replication protein A (RPA). RPA binds to ssDNA and acts as a gatekeeper to direct the ssDNA towards downstream DNA metabolic pathways with exceptional specificity. Understanding the mechanistic basis for such RPA-dependent functional specificity requires knowledge of the structural conformation of ssDNA when RPA-bound.

Skipping events impose repeated binding attempts: profound kinetic implications of protein-DNA conformational changes.

The kinetics of protein-DNA recognition, along with its thermodynamic properties, including affinity and specificity, play a central role in shaping biological function. Protein-DNA recognition kinetics are characterized by two key elements: the time taken to locate the target site amid various nonspecific alternatives; and the kinetics involved in the recognition process, which may necessitate overcoming an energetic barrier. In this study, we developed a coarse-grained (CG) model to investigate interactions between a transcription factor called the sex-determining region Y (SRY) protein and DNA, in order to probe how DNA conformational changes affect SRY-DNA recognition and binding kinetics.

Ordered and disordered regions of the Origin Recognition Complex direct differential in vivo binding at distinct motif sequences.

The Origin Recognition Complex (ORC) seeds replication-fork formation by binding to DNA replication origins, which in budding yeast contain a 17bp DNA motif. High resolution structure of the ORC-DNA complex revealed two base-interacting elements: a disordered basic patch (Orc1-BP4) and an insertion helix (Orc4-IH). To define the ORC elements guiding its DNA binding in vivo, we mapped genomic locations of 38 designed ORC mutants, revealing that different ORC elements guide binding at different sites.

Rapid Long-distance Migration of RPA on Single Stranded DNA Occurs Through Intersegmental Transfer Utilizing Multivalent Interactions.

Replication Protein A (RPA) is asingle strandedDNA(ssDNA)binding protein that coordinates diverse DNA metabolic processes including DNA replication, repair, and recombination. RPA is a heterotrimeric protein with six functional oligosaccharide/oligonucleotide (OB) domains and flexible linkers. Flexibility enables RPA to adopt multiple configurations andis thought to modulate its function.

Sound-mediated nucleation and growth of amyloid fibrils.

Unlabelled: Mechanical energy, specifically in the form of ultrasound, can induce pressure variations and temperature fluctuations when applied to an aqueous media. These conditions can both positively and negatively affect protein complexes, consequently altering their stability, folding patterns, and self-assembling behavior. Despite much scientific progress, our current understanding of the effects of ultrasound on the self-assembly of amyloidogenic proteins remains limited.

Cross-Talk of Cation-π Interactions with Electrostatic and Aromatic Interactions: A Salt-Dependent Trade-off in Biomolecular Condensates.

Biomolecular condensates are essential for cellular functionality, yet the complex interplay among the diverse molecular interactions that mediate their formation remains poorly understood. Here, using coarse-grained molecular dynamics simulations, we address the contribution of cation-π interactions to the stability of condensates formed via liquid-liquid phase separation. We found greater stabilization of up to 80% via cation-π interactions in condensates formed from peptides with higher aromatic residue content or less charge clustering.

Not Only Expansion: Proline Content and Density Also Induce Disordered Protein Conformation Compaction.

Intrinsically disordered proteins (IDPs) adopt a wide array of different conformations that can be constrained by the presence of proline residues, which are frequently found in IDPs. To assess the effects of proline, we designed a series of peptides that differ with respect to the number of prolines in the sequence and their organization. Using high-resolution atomistic molecular dynamics simulations, we found that accounting for whether the proline residues are clustered or isolated contributed significantly to explaining deviations in the experimentally-determined gyration radii of IDPs from the values expected based on the Flory scaling-law.

Conformational Analysis of Charged Homo-Polypeptides.

Many proteins have intrinsically disordered regions (IDRs), which are often characterized by a high fraction of charged residues with polyampholytic (i.e., mixed charge) or polyelectrolytic (i.

Negatively charged, intrinsically disordered regions can accelerate target search by DNA-binding proteins.

In eukaryotes, many DNA/RNA-binding proteins possess intrinsically disordered regions (IDRs) with large negative charge, some of which involve a consecutive sequence of aspartate (D) or glutamate (E) residues. We refer to them as D/E repeats. The functional role of D/E repeats is not well understood, though some of them are known to cause autoinhibition through intramolecular electrostatic interaction with functional domains.

Protein Diffusion Along Protein and DNA Lattices: Role of Electrostatics and Disordered Regions.

Diffusion is a pervasive process present in a broad spectrum of cellular reactions. Its mathematical description has existed for nearly two centuries and permits the construction of simple rules for evaluating the characteristic timescales of diffusive processes and some of their determinants. Although the term diffusion originally referred to random motions in three-dimensional (3D) media, several biological diffusion processes in lower dimensions have been reported.

Electron transport tyrosine-doped oligo-alanine peptide junctions: role of charges and hydrogen bonding.

A way of modulating the solid-state electron transport (ETp) properties of oligopeptide junctions is presented by charges and internal hydrogen bonding, which affect this process markedly. The ETp properties of a series of tyrosine (Tyr)-containing hexa-alanine peptides, self-assembled in monolayers and sandwiched between gold electrodes, are investigated in response to their protonation state. Inserting a Tyr residue into these peptides enhances the ETp carried their junctions.

Conformational Change of Transcription Factors from Search to Specific Binding: A Repressor Case Study.

In a process known as facilitated diffusion, DNA-binding proteins find their target sites by combining three-dimensional diffusion and one-dimensional scanning of the DNA. Following the trade-off between speed and stability, agile exploration of DNA requires loose binding, whereas, at the DNA target site, the searching protein needs to establish tight interactions with the DNA. To enable both efficient search and stable binding, DNA-binding proteins and DNA often switch conformations upon recognition.