Biology subjects

Habibullah, S.

Publications and source records attributed to Habibullah, S..

4 recordsLinked to original sources

bioRxiv2026

Mg2+-Dependent Multistep Folding and Stabilization of the GAAA Tetraloop-Receptor Interaction in a Group I Intron

Group I Introns are non-coding regions of pre-mRNA that catalyze their splicing from the RNA sequence by folding to a specific structure. We used computer simulations to study the folding mechanism of the P4-P6 domain in the Tetrahymena thermophila group I intron, focusing on the GAAA tetraloop-receptor (TL-R) interaction, which is a ubiquitous tertiary interaction in RNA structures. We show that the intron folds via a multistep pathway, populating seven states with distinct tertiary contacts. Under physiological Mg2+ concentrations ([Mg2+]), the loop-bulge-P4 tertiary interaction is essential to stabilize the docked TL-R complex, whereas in high [Mg2+], the TL-R complex is stable by itself. The solvated Mg2+ ions modulate the TL-R docking-undocking dynamics and stabilize non-native intermediate states. The condensation of Mg2+ in the major grooves of the TL and R helices is critical for them to attain specific stiffness essential for their facile docking. The results highlight the critical role of Mg2+ ions in facilitating TL-R interaction formation, which stabilizes long-range tertiary contacts in RNA structures. For Table of Contents Use Only O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/700762v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@142852org.highwire.dtl.DTLVardef@1632ad1org.highwire.dtl.DTLVardef@190021aorg.highwire.dtl.DTLVardef@17a1261_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

Dimerization Mechanism of HIV-1 RNA Hairpins to Extended Duplex Structures

Genomic RNA (gRNA) dimerization is essential for retroviral replication. In the gRNA of human immunodeficiency virus (HIV-1), the hairpin-like dimerization initiation sequence (DIS) forms a kissing-complex (KC) with the DIS sequence in another gRNA, which later converts into a stable extended-duplex (ED). Using coarse-grained simulations, we mapped the transition of HIV-1 DIS RNA hairpins (HPs) to ED and identified multiple intermediates beyond the KC. The KC has an anionic pocket stabilized through the condensation of Mg2+ ions. Hence, when only K+ ions are present at physiological levels, the HPs to ED transitions occur through a different dominant pathway devoid of the KC. We also observed purine base flipping near KC hydrogen bonds, revealing the population of a sub-ensemble of intermediates. The proposed dimerization mechanism of HPs to ED, along with the sub-ensemble of KC conformations and its anionic pocket, provides a strategic framework for designing specific retroviral drugs targeting this pathway. For Table of Contents Use Only O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/683870v1_ufig1.gif" ALT="Figure 1"> View larger version (94K): org.highwire.dtl.DTLVardef@2cb0f5org.highwire.dtl.DTLVardef@15c8d1org.highwire.dtl.DTLVardef@3321cborg.highwire.dtl.DTLVardef@efd30d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

Transition Metal Binding Drives Folding of a Metalloregulatory Riboswitch by Modulating Conformational Flexibility at Helical Junctions

Transition metal ions are crucial for bacterias survival. Bacteria employ metalloregulatory riboswitches to respond to varying metal ion concentrations. The czcD (NiCo) transcription riboswitch specifically senses Co2+, Ni2+, and Fe2+ ions at micromolar concentrations amid millimolar Mg2+. We used computer simulations with multi-resolution RNA models to understand how global conformational changes in the NiCo riboswitch are coupled to the remarkable specific binding of Co2+. We show that the riboswitch folds through an intermediate state, where a partially folded four-way junction (4WJ) creates an anionic pocket large enough to accommodate the binding of solvated divalent ions. The binding of Co2+ is coupled to the stability of the weak non-canonical G{middle dot}A base pairs at the helical junction that drive the formation of native-like coaxial stacking of four helices. The Co2+ binding further twists the 4WJ, which locks the ions in the bound state. Electronic structure calculations show that enhanced orbital interactions between conserved guanines in the 4WJ and Co2+ are responsible for the high specificity of the riboswitch in binding to Co2+ over Mg2+. We provide a framework for understanding and engineering tunable RNA-based biosensors and developing antimicrobials, as metal intoxication is an evolutionary strategy to inhibit bacterial growth.

biophysics↗

bioRxiv2024

Metal Ion Sensing by Tetraloop-Like RNA Fragment: Role of Compact Intermediates with Non-Native Metal Ion-RNA Inner Shell Contacts

Divalent metal ions influence the folding and function of RNA in the cells. The mechanism of how RNA structural elements in riboswitches sense specific metal ions is unclear. RNA interacts with ions through two distinct binding modes: direct interaction between the ion and RNA (inner-shell (IS) coordination) and indirect interaction between the ion and RNA mediated through water molecules (outer-shell (OS) coordination). To understand how RNA senses metal ions such as Mg2+ and Ca2+, we studied the folding of a small RNA segment from the Mg2+ sensing M-Box riboswitch using computer simulations. This RNA segment has the characteristics of a GNRA tetraloop motif and interestingly requires binding of a single Mg2+ ion. The folding free energy surface of this simple tetraloop system is multidimensional, with a population of multiple intermediates where the tetraloop and cation interact through IS and OS coordination. The partially folded compact tetraloop intermediates form multiple non-native IS contacts with the metal ion. Thermal fluctuations should break these strong non-native IS contacts so that the tetraloop can fold to the native state, resulting in higher folding free energy barriers. Ca2+ undergoes rapid OS to IS transitions and vice-versa due to its lower charge density than Mg2+. However, the ability of Ca2+ to stabilize the native tetraloop state is weaker as it could not hold the loop-closing nucleotides together due to its weaker interactions with the nucleotides. These insights are critical to understanding the specific ion sensing mechanisms in riboswitches, and the predictions are amenable for verification by NMR experiments.

biophysics↗