The COVID-19 pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an urgent need for effective therapeutic interventions. The spike glycoprotein of the SARS-CoV-2 is crucial for infiltrating host cells, rendering it a key candidate for drug development. By interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor, the spike initiates the infection of SARS-CoV-2. Linoleate is known to bind the spike glycoprotein, subsequently reducing its interaction with ACE2. However, the detailed kinetics underlying the protein-ligand interaction ..read more

This paper introduces a mathematical model for the growth of TDP-43 inclusion bodies. The model's equations make it possible to determine numerically the concentrations of TDP-43 dimers, monomers, and aggregates. Assuming that all aggregates integrate into the inclusion bodies, the model predicts the size of TDP-43 inclusion bodies. In the scenario where protein degradation machinery is dysfunctional, resulting in infinite half-lives for TDP-43 dimers, monomers, and aggregates, an approximate solution of the model equations is derived. This solution, valid for large times, predicts that the in ..read more

The structurally disordered intracellular loops (ICLs) of G protein-coupled receptors (GPCRs) play a critical role in G protein coupling. In our previous work, we used a combination of FRET-based and computational methodologies to show that the third intracellular loop (ICL3) modulates the activity and G protein coupling selectivity in GPCRs. In the current study, we have uncovered the role of several lipid components in modulating the conformational ensemble of ICL3 of the beta2-adrenergic receptor (B2AR). Our findings indicate that phosphatidylinositol 4,5-bisphosphate (PIP2) in the inner le ..read more

Biological condensates play a vital role in organizing cellular chemistry. They selectively partition biomolecules, preventing unwanted cross-talk and buffering against chemical noise. Intrinsically disordered proteins (IDPs) serve as primary components of these condensates due to their flexibility and ability to engage in multivalent, nonspecific interactions, leading to spontaneous aggregation. Theoretical advancements are critical at connecting IDP sequences with condensate emergent properties to establish the so-called molecular grammar. We proposed an extension to the stickers and spacers ..read more

Excitatory neurotransmission is principally mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). Dysregulation of AMPARs is the cause of many neurological disorders and how therapeutic candidates such as negative allosteric modulators inhibit AMPARs is unclear. Here, we show that non-competitive inhibition desensitizes AMPARs to activation and prevents positive allosteric modulation. We dissected the noncompetitive inhibition mechanism of action by capturing AMPARs bound to glutamate and the prototypical negative allosteric modulator, GYKI-52466, with cryo-electron microscopy. Non ..read more

Bimolecular cell membranes play a crucial role in many biological processes and possess a unique set of physical properties. Bimolecular membranes and monomolecular films can be considered as a "two-dimensional fluid" because the diffusion of molecules along the membrane or film is a hydrodynamic process. On the other hand, the bending of the cell membrane is controlled by its stiffness and elastic tension. The aim of this work is to adapt the Navier-Stokes hydrodynamic equations, obtained using the classical Chapman-Enskog method, to the case of two-dimensional membranes. The hydrodynamic equ ..read more

DEAD-box helicases, which are crucial for many aspects of RNA metabolism, often contain intrinsically disordered regions (IDRs), whose functions remain unclear. Using multiparameter confocal microscopy, we reveal that sex chromosome-encoded homologous RNA helicases, DDX3X and DDX3Y, form nano-sized RNA-protein clusters (RPCs) that foster their catalytic activities in vitro and in cells. The IDRs are critical for the formation of these RPCs. A thorough analysis of the catalytic cycle of DDX3X and DDX3Y by ensemble biochemistry and single molecule photon bursts in the confocal microscope showed ..read more

We study the influence of tyrosine phosphorylation on PTP-PEST, a cytosolic protein tyrosine phosphatase. Utilizing a combination of experimental data and computational modeling, specific tyrosine sites, notably Y64 and Y88, are identified for potential phosphorylation. Phosphorylation at these sites affects loop dynamics near the catalytic site, altering interactions among key residues and modifying the size of binding pocket. This, in turn, impacts substrate binding, as indicated by changes in binding energy. Our findings provide insights into the structural and functional consequences of ty ..read more

To what extent can evolution be considered as the sole first principle that explains all properties of nervous systems? This paper proposes an innovative, mathematically rigorous perspective on understanding nervous systems from an evolutionary perspective, leveraging methods of nonequilibrium statistical physics. This approach allows for modeling an exhaustive evolutionary optimization of nervous systems irrespective of any specific molecular and cellular mechanisms, approximate neuronal models or evolutionary history events. This novel method may shed light on key properties of biological ne ..read more

Biological membranes play key roles in cellular compartmentalization, structure, and its signaling pathways. At varying temperatures, individual membrane lipids sample from different configurations, a process that frequently leads to higher-order phase behavior and phenomena. Here we present a persistent homology-based method for quantifying the structural features of individual and bulk lipids, providing local and contextual information on lipid tail organization. Our method leverages the mathematical machinery of algebraic topology and machine learning to infer temperature-dependent structur ..read more