Biology subjects

Kirpichnikov, M. P.

Publications and source records attributed to Kirpichnikov, M. P..

4 recordsLinked to original sources

bioRxiv2025

(Re)defining the human chromatome: an integrated meta-analysis of localization, function, abundance, physical properties and domain composition of chromatin proteins

The full complement of chromatin-associated proteins--collectively referred to as the chromatome--enables genome functioning in eukaryotes by participating in a wide range of physico-chemical processes. These include mediating diverse specific and non-specific intermolecular interactions, catalyzing in situ synthesis and modification of macromolecules, facilitating ATP-dependent chromatin remodeling, etc. Despite considerable progress in epigenomics and the structural characterization of many nuclear proteins and their complexes, our understanding of chromatin organization at the proteome scale remains incomplete. This gap hinders the development of a holistic view of genome regulation. In this study, we present a state-of-the-art characterization of the human chromatome based on an integrative meta-analysis of diverse data sources describing the composition, abundance, and sub-nuclear localization of chromatin proteins. This effort is complemented by original analyses of their physico-chemical properties, domain architectures, and interaction patterns. To support and streamline these analyses, we developed a reference dataset of chromatin proteins, integrated with an empirical, function-based classification ontology and an associated interactive web resource -- SimChrom -- accessible at https://simchrom.intbio.org/. The reference dataset was carefully curated by reconciling data among protein databases, localization, and mass spectrometry-based experimental studies. Sequence-based and AI-assisted structural analyses revealed previously unannotated domains within chromatin proteins that warrant experimental validation, as well as the widespread use of multivalent interaction strategies that underpin chromatin organization. Together, our findings establish a robust framework for future studies aimed at elucidating genome function through detailed analysis of protein-protein and protein-nucleic acid interactions within chromatin. KEY POINTSO_LIThe first comprehensive meta-analysis of human chromatin proteins that bridges diverse data types C_LIO_LIEstablished an interactive SimChrom framework for chromatome research available for the community C_LIO_LIIdentified functionally relevant hallmarks of chromatin protein organization C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/680841v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@899feorg.highwire.dtl.DTLVardef@b62f3corg.highwire.dtl.DTLVardef@d72419org.highwire.dtl.DTLVardef@83037d_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

systems biology↗

bioRxiv2021

ATP-Independent Nucleosome Unfolding by FACT: Electron Microscopy Analysis

FACT is a histone chaperone that unfolds nucleosomes without ATP hydrolysis. We used electron microscopy to study FACT and FACT:nucleosome complexes, and found that both adopt broad ranges of configurations, indicating high flexibility. We found unexpectedly that the DNA binding protein Nhp6 also binds to the C-terminal tails of FACT subunits, inducing more open geometries of FACT even in the absence of nucleosomes. Nhp6 therefore supports nucleosome unfolding by altering both FACT structure and nucleosome properties. Complexes formed with FACT, Nhp6, and nucleosomes also produced a broad range of structures, revealing a large number of potential intermediates along a proposed unfolding pathway. The data suggest that Nhp6 has multiple roles before and during nucleosome unfolding by FACT, and that the process proceeds through a series of energetically similar intermediate structures, ultimately leading to an extensively unfolded form. One Sentence SummaryElectron microscopy reveals the pathway of ATP-Independent nucleosome unfolding by histone chaperone FACT.

molecular biology↗

bioRxiv2021

Effects of Mutations in the Receptor-Binding Domain of SARS-CoV-2 Spike on its Binding Affinity to ACE2 and Neutralizing Antibodies Revealed by Computational Analysis

SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) is responsible for one of the most deleterious pandemics of our time. The interaction between the ACE2 receptors at the surface of human cells and the viral Spike (S) protein triggers the infection making the receptor-binding domain (RBD) of the SARS-CoV-2 S-protein a focal target for the neutralizing antibodies (Abs). Despite the recent progress in the development and deployment of vaccines, the emergence of novel variants of SARS-CoV-2 insensitive to Abs produced in response to the vaccine administration and/or monoclonal ones represents upcoming jeopardy. Here, we assessed the possible effects of single and multiple mutations in the RBD of SARS-CoV-2 S-protein on its binding energy to various antibodies and the human ACE2 receptor. The performed computational analysis indicates that while single amino acid replacements in RBD may only cause partial impairment of the Abs binding, moreover, limited to specific epitopes, some variants of SARS-CoV-2 (with as few as 8 mutations), which are already present in the population, may potentially result in a much broader antigenic escape. We also identified a number of point mutations, which, in contrast to the majority of replacements, reduce RBD affinity to various antibodies without affecting its binding to ACE2. Overall, the results provide guidelines for further experimental studies aiming at the identification of the high-risk RBD mutations allowing for an antigenic escape.

biophysics↗

bioRxiv2021

Histone dynamics mediate DNA unwrapping and sliding in nucleosomes: insights from multi-microsecond molecular dynamics simulations

Nucleosomes are elementary building blocks of chromatin in eukaryotes. They tightly wrap ~147 DNA base pairs around an octamer of histone proteins. How nucleosome structural dynamics affect genome functioning is not completely clear. Here we report all-atom molecular dynamics simulations of nucleosome core particles at a timescale of 15 microseconds. At this timescale, functional modes of nucleosome dynamics such as spontaneous nucleosomal DNA breathing, unwrapping, twisting, and sliding were observed. We identified atomistic mechanisms of these processes by analyzing the accompanying structural rearrangements of the histone octamer and histone-DNA contacts. Octamer dynamics and plasticity were found to enable DNA unwrapping and sliding. Through multi-scale modeling, we showed that nucle-osomal DNA dynamics contribute to significant conformational variability of the chromatin fiber at the supranucleosomal level. Our study further supports mechanistic coupling between fine details of histone dynamics and chromatin functioning, provides a framework for understanding the effects of various chromatin modifications. We developed a web site for an interactive preview of molecular dynamics trajectories at https://intbio.github.io/Armeev_et_al_2021.

biophysics↗