Biology subjects

Sahakyan, H.

Publications and source records attributed to Sahakyan, H..

12 recordsLinked to original sources

bioRxiv2026

Computational modeling of an RNA-peptide world

Emergence and evolution of functional RNA and protein structures are the central problems for understanding the origin of life. Although it is well known that catalytically active RNA elements, ribozymes, can catalyze many reactions, including peptide bond formation, the specifics of the transition from the hypothetical, primordial RNA world to protein-based life centered at the translation system remain enigmatic. We developed AMES, Atomistic Molecular Evolution Simulator, and employed it to perform computer simulations of the evolution of short RNA molecules and RNA-peptide complexes. Comparison of the evolutionary trajectories and the structures of RNA molecules and RNA-peptide complexes emerging in these simulations shows that short random peptides accelerate RNA evolution, stabilize RNA folds, and boost the structural diversity of evolving RNA molecules, potentially enabling a broader range of activities. We hypothesize that the RNA world was, actually, an RNA-peptide world, in which, from the earliest stages of evolution, evolving RNA molecules interacted with short random peptides synthesized in a non-templated manner. These interactions could drive the evolution of diverse RNA structures and activities, and eventually, of the translation machinery.

evolutionary biology↗

bioRxiv2025

Mosquito vector ecologies are destabilizing as a result of climate change

Mosquito-borne infectious disease is a major cause of mortality and a significant economic burden worldwide. Shifting regional and seasonal patterns make proactive intervention challenging. Here we introduce a machine learning approach trained on satellite and mosquito observational data, improving generalizability to sparse observations while retaining similar positive performance characteristics of models used in standard practice. We provide global estimates for Aedes habitability at high spatial resolution in five-year increments from 1970-2024. The vast majority of ecologies appear to be destabilizing. Overall, we demonstrate a decrease in risk near the equator and an increase in risk in historically temperate climates including the United States, the European Union, and China. Despite this decrease in risk relative to historical averages, regions near the equator remain among the highest risk worldwide. Together, these results reflect an overall, marked expanse of the regions of the globe that support Aedes mosquitos and we observe an ongoing, linear increase in the global population at risk of contracting mosquito-borne disease.

ecology↗

bioRxiv2025

YprA family helicases provide the missing link between diverse prokaryotic immune systems

Bacteria and archaea possess an enormous variety of antivirus immune systems that often share homologous proteins and domains, some of which contribute to diverse defense strategies. YprA family helicases are central to widespread defense systems DISARM, Dpd, and Druantia. Here, through comprehensive phylogenetic and structural prediction analysis of the YprA family, we identify several major, previously unrecognized clades, with unique signatures of domain architecture and associations with other genes. Each YprA family clade defines a distinct class of defense systems, which we denote ARMADA (disARM-related Antiviral Defense Array), BRIGADE (Base hypermodification and Restriction Involving Genes encoding ARMADA-like and Dpd-like Effectors), or TALON (TOTE-like and ARMADA-Like Operon with Nuclease). In addition to the YprA-like helicase, ARMADA systems share two more proteins with DISARM. However, ARMADA YprA homologs are most similar to those of Druantia, suggesting ARMADA is a missing link connecting DISARM and Druantia. We show experimentally that ARMADA protects bacteria against a broad range of phages via a direct, non-abortive mechanism. We also discovered multiple families of satellite phage-like mobile genetic elements that often carry both ARMADA and Druantia Type III systems and show that these can provide synergistic resistance against diverse phages.

microbiology↗

bioRxiv2025

Protein structure alignment significance is often exaggerated

Machine learning has generated millions of high-quality predicted protein structures, creating a need for computationally efficient structure search algorithms and robust estimates of statistical significance at this scale. We show that unrelated proteins have a universal tendency towards convergent evolution of secondary and tertiary motifs, causing an excess of high-scoring false positive alignments. We investigate popular structure search and alignment algorithms, finding that previous methods routinely overestimate significance by up to six orders of magnitude. To address these issues, and to accommodate recent innovations in search algorithm design, we describe a novel method for estimating statistical significance. We show that its E-values are accurate, scale successfully with database size, and are robust against the (generally unknown) diversity of folds in the database. We implement our approach in an online structure search service based on Reseek at https://reseek.online.

bioinformatics↗

bioRxiv2024

In silico evolution of globular protein folds from random sequences

The origin and evolution of protein folds are among the most challenging, long-standing problems in biology 1,2. Although many plausible scenarios of early protein evolution leading to fold nucleation have been proposed 3-8, realistic simulation of this process was not feasible because of the lack of efficient approaches for protein structure prediction, a situation that changed with the advent of powerful tools for fast and robust protein structure prediction, such as AlphaFold 9,10 and ESMFold11. We developed a computational approach for protein fold evolution simulator (PFES) with atomistic details that provide insights into the mechanisms of evolution of globular folds from random amino acid sequences. PFES introduces random mutations in a population of protein sequences, evaluates the effect of mutations on protein structure, and selects a new set of proteins for further evolution. Repeating this process iteratively allows tracking the evolutionary trajectory of a changing protein fold that evolves under selective pressure for protein fold stability, interaction with other proteins, or other features shaping the fitness landscape. We employed PFES to show how globular protein folds could evolve from random amino acid sequences as monomers or in complexes with other proteins. The simulations reproduce the evolution of many simple folds of natural proteins as well as the evolution of distinct folds not known to exist in nature. We show that evolution of a stable fold from random sequences, on average takes 3 to 8 amino acid replacements per site, suggesting that simple but stable protein folds can evolve relatively easily. These findings could shed light on the enigma of the rapid evolution of protein fold diversity at the earliest stages of life evolution. PFES tracks the complete evolutionary history from simulations that describes intermediate states at the sequence and structure levels and can be used to test versatile hypotheses on protein fold evolution.

evolutionary biology↗

bioRxiv2024

The protein structurome of Orthornavirae and its dark matter

Metatranscriptomics is uncovering more and more diverse families of viruses with RNA genomes comprising the viral kingdom Orthornavirae in the realm Riboviria. Thorough protein annotation and comparison are essential to get insights into the functions of viral proteins and virus evolution. In addition to sequence- and hmm profile-based methods, protein structure comparison adds a powerful tool to uncover protein functions and relationships. We constructed an Orthornavirae structurome consisting of already annotated as well as unannotated ( dark matter) proteins and domains encoded in viral genomes. We used protein structure modeling and similarity searches to illuminate the remaining dark matter in hundreds of thousands of orthornavirus genomes. The vast majority of the dark matter domains showed either generic folds, such as single -helices, or no high confidence structure predictions. Nevertheless, a variety of lineage-specific globular domains that were new either to orthornaviruses in general or to particular virus families were identified within the proteomic dark matter of orthornaviruses, including several predicted nucleic acid-binding domains and nucleases. In addition, we identified a case of exaptation of a cellular nucleoside monophosphate kinase as an RNA-binding protein in several virus families. Notwithstanding the continuing discovery of numerous orthornaviruses, it appears that all the protein domains conserved in large groups of viruses have already been identified. The rest of the viral proteome seems to be dominated by poorly structured domains including intrinsically disordered ones that likely mediate specific virus-host interactions. IMPORTANCEAdvanced methods for protein structure prediction, such as AlphaFold2, greatly expand our capability to identify protein domains and infer their likely functions and evolutionary relationships. This is particularly pertinent for proteins encoded by viruses that are known evolve rapidly and as a result often cannot be adequately characterized by analysis of the protein sequences. We performed an exhaustive structure prediction and comparative analysis for uncharacterized proteins and domains ( dark matter) encoded by viruses with RNA genomes. The results show the dark matter of RNA virus proteome consists mostly of disordered and all -helical domains that cannot be readily assigned a specific function and that likely mediate various interactions between viral proteins and between viral and host proteins. The great majority of globular proteins and domains of RNA viruses are already known although we identified several unexpected domains represented in individual viral families.

evolutionary biology↗

bioRxiv2024

The Cryptic Bacterial Microproteome

Microproteins encoded by small open reading frames (smORFs) comprise the "dark matter" of proteomes. Although functional microproteins were identified in diverse organisms from all three domains of life, bacterial smORFs remain poorly characterized. In this comprehensive study of intergenic smORFs (ismORFs, 15-70 codons) in 5,668 bacterial genomes of the family Enterobacteriaceae, we identified 67,297 clusters of ismORFs subject to purifying selection. The ismORFs mainly code for hydrophobic, potentially transmembrane, unstructured, or minimally structured microproteins. Using AlphaFold Multimer, we predicted interactions of some of the predicted microproteins encoded by transcribed ismORFs with proteins encoded by neighboring genes, revealing the potential of microproteins to regulate the activity of various proteins, particularly, under stress. We compiled a catalog of predicted microprotein families with different levels of evidence from synteny analysis, structure prediction, and transcription and translation data. This study offers a resource for investigation of biological functions of microproteins. HighlightsO_LIThousands of previously unknown bacterial microproteins predicted C_LIO_LIMost microproteins belong to lineage-specific families, revealing unexplored diversity of bacterial proteomes C_LIO_LIComparative genome analysis suggests de novo emergence of numerous microproteins C_LIO_LIInteractions between stress-induced microproteins and known functional proteins predicted C_LIO_LIThis study provides a resource to investigate cryptic bacterial microproteomes C_LI

genomics↗

bioRxiv2023

Astonishing diversity and multifaceted biological connections of Type IV restriction-modification systems

A comprehensive census of McrBC systems, among the most common forms of prokaryotic Type IV restriction systems, followed by phylogenetic analysis, reveals their enormous abundance in diverse prokaryotes and a plethora of genomic associations. We focus on a previously uncharacterized branch, which we denote CoCoNuTs (coiled-coil nuclease tandems) for their salient features: the presence of extensive coiled-coil structures and tandem nucleases. The CoCoNuTs alone show extraordinary variety, with 3 distinct types and multiple subtypes. All CoCoNuTs contain domains predicted to interact with translation system components, such as OB-folds resembling the SmpB protein that binds bacterial transfer-messenger RNA (tmRNA), YTH-like domains that might recognize methylated tmRNA, tRNA, or rRNA, and RNA-binding Hsp70 chaperone homologs, along with RNases, such as HEPN domains, all suggesting that the CoCoNuTs target RNA. Many CoCoNuTs might additionally target DNA, via McrC nuclease homologs. Additional restriction systems, such as Type I RM, BREX, and Druantia Type III, are frequently encoded in the same predicted superoperons. In many of these superoperons, CoCoNuTs are likely regulated by cyclic nucleotides, possibly, RNA fragments with cyclic termini, that bind associated CARF (CRISPR-Associated Rossmann Fold) domains. We hypothesize that the CoCoNuTs, together with the ancillary restriction factors, employ an echeloned defense strategy analogous to that of Type III CRISPR-Cas systems, in which an immune response eliminating virus DNA and/or RNA is launched first, but then, if it fails, an abortive infection response leading to PCD/dormancy via host RNA cleavage takes over.

microbiology↗

bioRxiv2023

A generic binding pocket for small molecule IKs activators at the extracellular inter-subunit interface of KCNQ1 and KCNE1 channel complexes

The cardiac IKs ion channel comprises KCNQ1, calmodulin, and KCNE1 in a dodecameric complex which provides a repolarizing current reserve at higher heart rates and protects from arrhythmia syndromes that cause fainting and sudden death. Pharmacological activators of IKs are therefore of interest both scientifically and therapeutically for treatment of IKs loss-of-function disorders. One group of chemical activators are only active in the presence of the accessory KCNE1 subunit and here we investigate this phenomenon using molecular modeling techniques and mutagenesis scanning in mammalian cells. A generalized activator binding pocket is formed extracellularly by KCNE1, the domain-swapped S1 helices of one KCNQ1 subunit and the pore/turret region made up of two other KCNQ1 subunits. A few residues, including K41, A44 and Y46 in KCNE1, W323 in the KCNQ1 pore, and Y148 in the KCNQ1 S1 domain, appear critical for the binding of structurally diverse molecules, but in addition, molecular modeling studies suggest that induced fit by structurally different molecules underlies the generalized nature of the binding pocket. Activation of IKs is enhanced by stabilization of the KCNQ1-S1/KCNE1/pore complex, which ultimately slows deactivation of the current, and promotes outward current summation at higher pulse rates. Our results provide a mechanistic explanation of enhanced IKscurrents by these activator compounds and provide a map for future design of more potent therapeutically useful molecules.

pharmacology and toxicology↗

bioRxiv2022

Identification of branching order within the kingdom Bamfordvirae

The kingdom Bamfordvirae comprises the majority of the realm Varidnaviria and, according to the 2021 release of Virus Taxonomy by the International Committee on Taxonomy of Viruses, consists of the phyla Nucleocytoviricota and Preplasmiviricota. There are several fundamental unresolved issues related to the evolution of Bamfordvirae. These are questions concerning Bamfordvirae taxonomy including the branching order of Nucleocytoviricota and the question of the monophyly of Preplasmiviricota. Here, based on the analyses of the individual core protein phylogenies, supertree, concatenated trees, dendrograms, as well as superdendrogram, we have refined the branching order of major groups within phylum Nucleocytoviricota using the rooting of the entire phylum on the cellular outgroups. These efforts resulted in several major changes in Bamfordvirae phylogeny. In particular, we showed that Nucleocytoviricota consists of two sister clades, consisting of Phycodnaviridae sensu lato on the one hand and Mimiviridae sensu lato, Iridoviridae/Ascoviridae, Marseilleviridae, pithoviruses including Cedratvirus, Solumvirus, Solivirus, and Orpheovirus, Mininucleoviridae, Asfarviridae sensu lato, and Poxviridae on the other hand. According to our data, Asfarviridae sensu lato and Poxviridae have likely originated from within the class Megaviricetes. We gave evidence for polyphyly of the phylum Preplasmiviricota and argued for a transfer of the families Lavidaviridae, Adintoviridae, and Adenoviridae from the phylum Preplasmiviricota into the phylum Nucleocytoviricota. We also argued for the origin of the Nucleocytoviricota from small prokaryotic viruses and gave arguments against the origin of Nucleocytoviricota from the Adintoviridae/Polinton-like viruses. ImportanceThe monophyly of Varidnaviria, consisting of the Bamfordvirae and Helvetiavirae kingdoms, remains a matter of debate. To confirm or refute the monophyly of Varidnaviria, it is important to identify the sources of origin and phylogenetic relationships common to all Varidnaviria genes, such as the FtsK-HerA superfamily ATPases, major and minor capsid proteins. However, such studies are relevant only if the direction of evolution of both kingdoms was firmly established. Thus, our work, by clarifying the phylogenetic relationships within the Bamfordvirae kingdom, provided a solid basis for studying the evolutionary relationships of this kingdom with a vast diversity of supposedly related viruses outside of Bamfordvirae, including Helvetiavirae (Varidnaviria).

evolutionary biology↗

bioRxiv2020

Energy-dependent protein folding: modeling how a protein-folding machine may work

Proteins fold robustly and reproducibly in vivo, but many cannot fold in vitro in isolation from cellular components. The pathways to proteins native conformations, either in vitro or in vivo, remain largely unknown. The slow progress in recapitulating protein folding pathways in silico may be an indication of the fundamental deficiencies in our understanding of folding as it occurs in nature. Here we consider the possibility that protein folding in living cells may not be driven solely by the decrease in Gibbs free energy and propose that protein folding in vivo should be modeled as an active energy-dependent process. The mechanism of action of such protein folding machine might include direct manipulation of the peptide backbone. To show the feasibility of a protein folding machine, we conducted molecular dynamics simulations that were augmented by the application of mechanical force to rotate the C-terminal amino acid while simultaneously limiting the N-terminal amino acid movements. Remarkably, the introduction of this simple manipulation of peptide backbones to the standard molecular dynamics simulation indeed facilitated the formation of native structures in five diverse alpha-helical peptides. Such effect may play a role during co-translational protein folding in vivo: considering the rotating motion of the tRNA 3-end in the peptidyltransferase center of the ribosome, it is possible that this motion might introduce rotation to the nascent peptide and influence the peptides folding pathway in a way similar to what was observed in our simulations.

biochemistry↗

bioRxiv2020

AN ADMIXTURE SIGNAL IN ARMENIANS AROUND THE END OF THE BRONZE AGE REVEALS WIDESPREAD POPULATION MOVEMENT ACROSS THE MIDDLE EAST

The Armenians, a population inhabiting the region in West Asia known as the Armenian Highland, has been argued to show a remarkable degree of population continuity since the Early Neolithic. Here we test the degree of continuity of this population as well as its plausible origin, by collating modern and ancient genomic data, and adding a number of novel contemporary genomes. We show that Armenians have indeed remained unadmixed through the Neolithic and at least until the first part of the Bronze Age, and fail to find any support for historical suggestions by Herodotus of an input from the Balkans. However, we do detect a genetic input of Sardinian-like ancestry during or just after the Middle-Late Bronze Age. A similar input at approximately the same time was detected in East Africa, suggesting large-scale movement both North and South of the Middle East. Whether such large-scale population movement was a result of climatic or cultural changes is unclear, as well as the true source of gene flow remains an open question that needs to be addressed in future ancient DNA studies.

genomics↗