Biology subjects

Sheikhhassani, V.

Publications and source records attributed to Sheikhhassani, V..

4 recordsLinked to original sources

bioRxiv2025

PyMOL plugin for Protein Circuit Topology

Circuit Topology (CT) provides a fundamental framework for analysing folded polymer chains, with applications in functional annotation, protein engineering and drug development. We present a protein CT analysis plugin for PyMOL v3.1.6.1 with a graphical user interface (GUI), automatic installation, and novel features developed through integration with PyMOL's application programming interface (API). The plugin integrates various previously developed CT methodologies for studying structured proteins and their complexes as well as the dynamics of disordered proteins. Analysis of a representative protein and a molecular dynamics trajectory demonstrates the plugin's three analysis modes and their outputs. The plugin reproduces the reference ProteinCT implementation exactly on the structures tested, and is distributed with a versioned release, a pinned environment and a one-command reproduction of every result reported here.

bioinformatics↗

bioRxiv2025

Optically driven control of mechanochemistry and fusion dynamics of biomolecular condensates via thymine dimerization

Phase-separated biomolecular condensates serve as functional elements of biological cells, contribute to protocell formation in prebiotic systems during early life, and represent a distinct class of soft matter with a broad range of potential applications. Understanding and controlling condensate mechanochemistry is critical for their function and material properties. Photochemical processes, such as UV-induced chemical modifications, are ubiquitous in nature and can have both detrimental and constructive impacts on living systems, and are also readily implemented in engineering applications. However, how phase-separated condensate formation influences photochemical processes, and conversely, how photochemical reactions impact condensate dynamics, remains an open question. Combining scanning probe microscopy with optical imaging and control, we developed assays that enable the study of mechanical transitions and fusion dynamics in condensate droplets, revealing that UV-induced thymine dimerization alters condensate nucleation and coalescence. Depending on the frequency and topological arrangement of thymine dimers, particularly the balance between inter- and intrachain crosslinks, UV can induce a transition from liquid-like to solid-like behaviours or lead to aggregate formation. UV treatment also leads to compartmentalization in condensate systems by e.g., promoting the formation of arrested fusion droplets, which are stable against environmental changes. UV illumination can thus be leveraged to program the architecture and material properties of DNA-based biomolecular condensates, with implications for prebiotic chemistry, and bio-inspired engineering.

biophysics↗

bioRxiv2024

Polyglutamine expansion induced dynamic misfolding of Androgen Receptor

Spinal bulbar muscular atrophy (SBMA) is caused by a polyglutamine expansion (pQe) in the N-terminal transactivation domain of human androgen receptor (AR-NTD), resulting in a combination of toxic gain- and loss-of-function mechanisms. The structural basis of these processes has not been resolved due to the disordered nature of the NTD, which hinders experimental analyses of its detailed conformations. Here, using extensive computational modelling, we show that AR-NTD forms dynamic compact regions, which upon pQe re-organize dynamically, mediated partly by direct pQ interaction with the Androgen N-Terminal Signature (ANTS) motif. The altered dynamics of the NTD result in a perturbation of interdomain interactions, with potential implications for binding of the receptor protein to its response element. Oligomeric aggregation of the dynamic misfolded NTD exposes pQe, but blocks tau-5 and the FQNLF motif, which could lead to aberrant receptor transcriptional activity. These observations suggest a structural mechanism for AR dysfunction in SBMA.

pathology↗

bioRxiv2024

Correlating Protein Aggregate Structure with Cellular Function in Differentiated Muscle Cells: Discriminating Pathogenic from Non-Pathogenic Forms

Ageing has a major adverse impact on maintaining cellular proteostasis and age-related dysregulation leads to an increase in protein aggregation. Equivalently, the accumulation of aggregated proteins accelerates proteostasis impairment. Accumulation of protein aggregates and impaired proteostasis are hallmarks of ageing-associated neuromuscular disorders and tissue degeneration is predominantly in post-mitotic muscle and neuronal cells. A short alanine expansion mutation in the Poly(A) binding protein nuclear 1 (PABPN1) causes Oculopharyngeal muscular dystrophy (OPMD), a rare age-associated protein aggregation myopathy. PABPN1 is a vital RNA-binding protein but OPMD pathology is limited to skeletal muscles connected to nuclear aggregates. In contrast to the mutant PABPN1, the wild-type PABPN1 forms age-associated non-pathogenic aggregates. We generated an inducible muscle cell models for mutant and wild-type PABPN1 protein aggregation. By combining four different, but complementary, imaging modalities, covering micro- to nanoscale resolutions, we were able to characterise differences in structure and dynamics between pathogenic and non-pathogenic PABPN1 aggregates in differentiated muscle cells. These data allowed us to correlate the structure of aggregates to cellular function, providing important insights into how aggregates lead to cell dysfunction in post-mitotic cells. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/591067v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@22870corg.highwire.dtl.DTLVardef@d0616borg.highwire.dtl.DTLVardef@abe34dorg.highwire.dtl.DTLVardef@d7f359_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗