Biology subjects

Bonus, M.

Publications and source records attributed to Bonus, M..

4 recordsLinked to original sources

bioRxiv2026

LignAmb25: A Comprehensive AMBER Force Field Addressing Lignin's Structural and Chemical Diversity

LignAmb25 is a comprehensive force field for lignin molecular dynamics simulations implemented natively within the AMBER package. The force field includes parameters for all common monolignol units (p-coumaryl, coniferyl, caffeyl, and sinapyl alcohol) and their associated linkages ({beta}-O4, {beta}-5, {beta}-{beta}, {beta}-1, 5-5, 5-O4, -O4, BDO, and DBDO), along with less commonly encountered units such as tricin, spirodienones, and hydroxystilbenes. This enables simulations of both softwood and hardwood lignin structures with compositions that would be difficult to isolate experimentally. Force field parameters were initially derived from the GAFF2 force field and systematically optimized using quantum mechanical calculations at the {omega}B97X-D4/def2-TZVPP level of theory on conformer ensembles derived via the CREST/CENSO conformational sampling toolchain. Partial atomic charges were derived using the RESP methodology, consistent with AMBER conventions. Experimentally measured crystal structures of lignin simulated with LignAmb25 accurately retain their packing based on calculations of the RMSD and density error compared to the deposited crystal structure, thereby exceeding the performance of the lignin force field for CHARMM. Additionally, LignAmb25 is shown to reliably estimate the enthalpy of vaporization and the absolute hydration free energy of lignin-related compounds. The LignAmb25 force field is provided in two variants: LignAmb25Solo, a standalone version not meant for use with other biomolecular force fields that focuses on accurate modelling of lignin-solvent interactions, and LignAmb25HF, a version that is compatible with all other major biomolecular force fields in the AMBER molecular dynamics suite. This includes force fields of the GLYCAM (carbohydrates), ff19SB (proteins), and LIPID (lipids) families, as well as the DNA and RNA force fields routinely used in AMBER. The LignAmb25 force field will be distributed as of AMBER 26. Statement of significanceLignin, a complex aromatic heteropolymer comprising up to 40% of plant biomass, remains one of the most challenging biopolymers to characterize experimentally due to its structural heterogeneity, recalcitrance against depolymerization and selective chemical conversion, and lack of a defined primary sequence. Traditional wet-lab analytical methods face significant limitations, including lignins poor solubility, tendency to aggregate, and structural modifications during extraction and analysis. These experimental challenges make computational approaches essential for understanding the molecular basis of lignins physicochemical properties and for advancing lignocellulosic biomaterial applications. We present LignAmb25, a molecular mechanics force field for lignin implemented within AMBER, enabling researchers to investigate lignin structures and dynamics under conditions difficult to access experimentally. LignAmb25 integrates into the AMBER force field system and represents an alternative to the lignin force field for CHARMM. It improves upon the latter by including spirodienones and hydroxystilbenes as less commonly encountered monolignol units and the addition of several new linkages.

biophysics↗

bioRxiv2025

Molecular Insights into CLD Domain Dynamics and Toxin Recruitment of the HlyA E. coli T1SS

Escherichia coli is a Gram-negative opportunistic pathogen causing nosocomial infections through the production of various virulence factors. Type 1 secretion systems (T1SS) contribute to virulence by mediating one-step secretion of unfolded substrates directly into the extracellular space, bypassing the periplasm. A well-studied example is the hemolysin A (HlyA) system, which secretes the HlyA toxin in an unfolded state across the inner and outer membranes. T1SS typically comprise a homodimeric ABC transporter (HlyB), a membrane fusion protein (HlyD), and the outer membrane protein TolC. Some ABC transporters in T1SS also contain N-terminal C39 peptidase or peptidase-like (CLD) domains implicated in substrate interaction. Recent cryo-EM studies have resolved the inner-membrane complex as a trimer of HlyB homodimers with associated HlyD protomers. However, a full structural model including TolC remains unavailable. We present the first complete structural model of the HlyA T1SS, constructed using template- and MSA-based information and validated by SAXS. Molecular dynamics simulations provide insights into the function of the CLD domains, which are partially absent from existing cryo-EM structures. These domains may modulate transport by stabilizing specific conformations of the complex. Simulations with a C-terminal fragment of HlyA indicate that toxin binding occurs in the occluded conformation of HlyB, potentially initiating substrate transport through a single HlyB protomer before transitioning to an inward-facing state. HlyA binding also induces allosteric effects on HlyD, altering key residues involved in TolC recruitment. These results indicate how substrate recognition and transport are coupled and may support the development of antimicrobial strategies targeting the T1SS.

biophysics↗

bioRxiv2025

PyPE_RESP: A tool to facilitate and standardize derivation of RESP charges

We introduce PyPE_RESP, a tool to facilitate and standardize partial atomic charge derivation using the RESP approach. PyPE_RESP builds upon the open-source Python package RDKit for chemoinformatics and the AMBER suite for molecular simulations. PyPE_RESP provides an easy setup of multi-conformer and multi-molecule Restrained Electrostatic Potential (RESP) fitting while allowing a comprehensive definition of charge constraint groups through multiple methods. As a command line tool, PyPE_RESP can be integrated into batch processes. The software enables the derivation of partial atomic charges for additive and polarizable force fields. It outputs constraint group and non-constraint group charges to give an immediate overview of the fit result. PyPE_RESP will be distributed with AmberTools and compatible with most computing platforms. Table of Contents Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/631713v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@7fc123org.highwire.dtl.DTLVardef@16102f0org.highwire.dtl.DTLVardef@8044dorg.highwire.dtl.DTLVardef@5277f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

Impaired transitioning of the FXR ligand binding domain to an active state underlies a PFIC5 phenotype

Nuclear receptor farnesoid X receptor (FXR) acts as a key regulator of bile acid pool homeostasis and metabolism. Within the enterohepatic circulation, reabsorbed bile acids act as FXR agonists, which transcriptionally controls the synthesis and transport of bile acids. Binding occurs in the ligand binding domain (LBD), favoring a conformational change to the active state in which helix 12 interacts with the LBD to form an interaction surface for nuclear co-activators. The homozygous missense variant T296I, identified in a PFIC patient, is located close to the critical helix 12 interaction. Here, we identified reduced transcriptional activity of the variant protein on the downstream targets bile salt export pump (BSEP) and small heterodimer partner (SHP) in vitro, within the patients liver, and in iPSC-derived hepatic organoids. BSEP-dependent Tauro-DBD transport was impaired in T296I patient-derived organoids, but could be rescued via lipid nanoparticle-mediated FXR WT mRNA delivery, indicating the variant is responsible for the identified reduced BSEP expression. Using molecular dynamics simulations, we observed a reduced transitioning from the inactive to the active state for the T296I variant, indicating a molecular mechanism underlying the reduced activity. To our knowledge, this is the first study to describe the conformational change from an inactive to an active state of the FXR LBD. This might be useful for new therapeutic approaches targeting the activation of FXR.

physiology↗