Biology subjects

Jalalypour, F.

Publications and source records attributed to Jalalypour, F..

3 recordsLinked to original sources

bioRxiv2026

Chameleonicity Beyond Compactness: Conformational Persistence and Passive Permeability Across 20 PROTAC Ensembles

Proteolysis-targeting chimeras (PROTACs) are large, flexible molecules that frequently extend beyond conventional drug-like chemical space, including Lipinski's rule-of-five boundaries. Their membrane permeability has often been linked to molecular chameleonicity and the ability to adopt compact conformations with reduced polar surface exposure; however, the underlying conformational determinants remain unclear. Here, we investigated 20 PROTACs spanning distinct passive-permeability classes using enhanced-sampling molecular dynamics (ES-MD). All permeability classes accessed compact states with low radius of gyration (Rg) and polar surface area (PSA), indicating that compact-state accessibility alone does not distinguish permeable from non-permeable PROTACs. We therefore introduce maximum ring size (MRS), defined as the size of the largest intramolecular hydrogen-bonded ring, as a metric for identifying compact conformations stabilized by long-range intramolecular hydrogen bonding. Like the other descriptors examined, MRS neither separates nor ranks the permeability classes, but helps locate folded states in the large ensemble. Representative compact conformations from selected highly permeable, moderately permeable, and non-permeable compounds were subsequently examined by all-atom unbiased MD in water and chloroform. The highly permeable PROTAC held a closed-flat ensemble in both environments, but in two structurally distinct arrangements, whereas the other two redistributed across heterogeneous ensembles. Passive diffusion therefore appears to depend on the population, stability, and environment-dependent persistence of permeable-like states rather than on compactness alone.

biophysics↗

bioRxiv2024

An Allosteric Cholesterol Site in Glycine Receptors Characterized Through Molecular Simulations

Glycine receptors are pentameric ligand-gated ion channels that conduct chloride ions across postsynaptic membranes to facilitate fast inhibitory neurotransmission. In addition to gating by the glycine agonist, interactions with lipids and other compounds in the surrounding membrane environment modulate their function, but molecular details of these interactions remain unclear - in particular for cholesterol. To identify such interactions, here we report on coarse-grained simulations in a model neuronal membrane for three zebrafish glycine-receptor structures, representing apparent resting, open, and desensitized states. We then converted the systems to all-atom models to examine detailed lipid interactions, and observe cholesterol bound to the receptor at an outer-leaflet intersubunit site in a state-dependent manner, indicating that it can bias receptor function. Finally, using a modified perturbation-response scanning approach, we applied short atomistic simulations to identify amino-acid translations correlated with gating conformational changes. Frequent cholesterol contacts in atomistic simulations clustered with residues identified by perturbation analysis and overlapped with mutations influencing channel function and pathology. Cholesterol binding at this site was also observed in a recently reported pig heteromeric glycine receptor. These results indicate state-dependent lipid interactions relevant to allosteric transitions of heteromeric glycine receptors, including specific amino-acid contacts applicable to biophysical modeling and pharmaceutical design.

biophysics↗

bioRxiv2022

Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS

Undruggability of RAS proteins has necessitated alternative strategies for the development of effective inhibitors. In this respect, phosphorylation has recently come into prominence as this reversible post-translational modification attenuates sensitivity of RAS towards RAF. As such, in this study, we set out to unveil the impact of phosphorylation on dynamics of HRASWT and aim to invoke similar behavior in HRASG12D mutant by means of small therapeutic molecules. To this end, we performed molecular dynamics (MD) simulations using phosphorylated HRAS and showed that phosphorylation of Y32 distorted Switch I, hence the RAS/RAF interface. Consequently, we targeted Switch I in HRASG12D by means of approved therapeutic molecules and showed that the ligands enabled detachment of Switch I from the nucleotide-binding pocket. Moreover, we demonstrated that displacement of Switch I from the nucleotide-binding pocket was energetically more favorable in the presence of the ligand. Importantly, we verified computational findings in vitro where HRASG12D/RAF interaction was prevented by the ligand in HEK293T cells that expressed HRASG12D mutant protein. Therefore, these findings suggest that targeting Switch I, hence making Y32 accessible might open up new avenues in future drug discovery strategies that target mutant RAS proteins.

cancer biology↗