Biology subjects

Biriukov, D.

Publications and source records attributed to Biriukov, D..

7 recordsLinked to original sources

bioRxiv2025

Transient Formation of Supramolecular Complexes Between Hyaluronan and Oligopeptides at Submicromolar Concentration

Charged polymer interactions govern critical biological and technological processes by altering the structure and dynamics of the surrounding aqueous environment. How-ever, studying these interactions and the resulting environments across a broad concentration range is challenging, as it demands a combination of multiple techniques with varying resolutions and complex data interpretation. In particular, detecting interactions at submicromolar levels remains technically challenging, with most methods lacking the resolution required for molecular-level characterization. Here, we examined the interactions between high-molecular-weight hyaluronan (HA), a biologically and technologically relevant polymer, and a series of model oligopeptides--nonaarginine, nonalysine, and nonaglycine, chosen for their charge and side-chain chemistry. Using angle-resolved second harmonic scattering (AR-SHS), multi-angle dynamic light scattering, nuclear magnetic resonance spectroscopy, and all-atom molecular dynamics simulations, we captured a detailed molecular picture of HA-peptide interactions across a broad concentration range, including submicromolar concentrations. We found selective and multivalent interactions between HA and positively charged peptides, which are consistently stronger with nonaarginine. These interactions trigger significant solvent and solute remodeling, including nanoscale HA-peptide clustering. Our molecular simulations provide essential atomic-level interpretation of the experimental data, elucidating the transient and dynamic nature of the intermolecular interactions and the underlying processes of molecular aggregation and induced water reorientation. The distinct behavior found in arginine-rich peptides highlights their potential in modulating extracellular environments and as peptide-based drug delivery systems. Moreover, our methodological framework, combining sensitive AR-SHS signals with atomistic simulations and traditional structural techniques, offers unprecedented molecular insight into complex polymer-peptide interactions, laying the groundwork for future research on dynamic supramolecular systems in soft materials and unstructured biological environments such as the extracellular matrix.

biophysics↗

bioRxiv2024

The Origins of Arginine "Magic": Guanidinium Like-Charge Ion Pairing and Oligoarginine Aggregation in Water by NMR, Cryoelectron Microscopy, and Molecular Dynamics Simulations

The phenomenon of like-charge pairing of hydrated ions is a physical manifestation of the unique solvation properties of certain ion pairs in water. Waters high dielectric constant and related ion screening capability significantly influence the interaction between like-charged ions, with the possibility to transform it - in some cases - from repulsion to attraction. Guanidinium cations (Gdm+) represent a quintessential example of such like-charge pairing due to their specific geometry and charge distribution. In this work, we present experimental quantification of Gdm+-Gdm+ contact ion pairing in water utilizing nuclear magnetic resonance (NMR) spectroscopy experiments complemented by molecular dynamics (MD) simulations and density functional theory (DFT) calculations. The observed interaction is very weak -- about -0.5 kJ{middle dot}mol-1 -- which aligns with theoretical estimation from MD simulations. We also contrast the behavior of Gdm+ with NH4+ cations, which do no exhibit contact ion pairing in water. DFT calculations predict that the NMR chemical shift of Gdm+ dimers is smaller than that of monomers, in agreement with NMR titration curves that display a non-linear Langmuir-like behavior. Additionally, we conducted cryo-electron microscopy experiments on oligoarginines R9, which (unlike nona-lysines K9) exhibit aggregation in water. This points again to like charge pairing of the guanidinium side chain groups, as corroborated also by molecular dynamics simulations of these peptides in water.

biophysics↗

bioRxiv2024

Developing and Benchmarking Sulfate and Sulfamate Force Field Parameters for Glycosaminoglycans via Ab Initio Molecular Dynamics Simulations

Glycosaminoglycans (GAGs) are negatively charged polysaccharides found on cell surfaces, where they regulate transport pathways of foreign molecules toward the cell. The structural and functional diversity of GAGs is largely attributed to varied sulfa-tion patterns along the polymer chains, which makes understanding their molecular recognition mechanisms crucial. Molecular dynamics (MD) simulations, with their un-matched microscopic perspective, have the potential to be a reference tool for exploring the patterns responsible for biologically relevant interactions. However, the capability of molecular dynamics models (i.e., force fields) used in biosimulations to accurately capture sulfation-specific interactions is not well established. In this work, we evalu-ate the performance of molecular dynamics force fields for sulfated GAGs by studying ion pairing of Ca2+ to sulfated moieties -- N-methylsulfamate and methylsulfate -- that resemble N- and O-sulfation found in GAGs, respectively. We tested nonpolariz-able (CHARMM36 and GLYCAM06), explicitly polarizable (Drude and AMOEBA), and implicitly polarizable through charge scaling (prosECCo75 and GLYCAM-ECC75) force fields. The Ca-sulfamate/sulfate interaction free energy profiles obtained with the tested force fields were compared against reference ab initio molecular dynamics (AIMD) simulations. AIMD reveals that the preferential Ca2+ binding mode to sul-fated GAG groups is solvent-shared pairing, and only the charge-scaled models agree satisfactorily with the AIMD data. All other force fields exhibit poorer performance, sometimes even qualitatively. Surprisingly, even explicitly polarizable force fields dis-play a notable shortfall in their performance, attributed to difficulties in their optimiza-tion and possible inherent limitations in depicting high-charge-density ion interactions accurately. Finally, the underperforming force fields lead to unrealistic aggregation of sulfated saccharides, qualitatively distorting our understanding of the soft glycocalyx environment. Our results highlight the importance of accurately treating electronic polarization in MD simulations of sulfated GAGs and caution against over-reliance on currently available models without thorough validation and optimization.

biophysics↗

bioRxiv2024

Effective Inclusion of Electronic Polarization Improves the Description of Electrostatic Interactions: The prosECCo75 Biomolecular Force Field

prosECCo75 is an optimized force field effectively incorporating electronic polarization via charge scaling. It aims to enhance the accuracy of nominally nonpolarizable molecular dynamics (MD) simulations for interactions in biologically relevant systems involving water, ions, proteins, lipids, and saccharides. Recognizing the inherent limitations of nonpolarizable force fields in precisely modeling electrostatic interactions essential for various biological processes, we mitigate these shortcomings by accounting for electronic polarizability in a physical rigorous mean-field way that does not add to computational costs. With this scaling of (both integer and partial) charges within the CHARMM36 framework, prosECCo75 addresses overbinding artifacts. This improves agreement with experimental ion binding data across a broad spectrum of systems -- lipid membranes, proteins (including peptides and amino acids), and saccharides -- without compromising their biomolecular structures. prosECCo75 thus emerges as a computationally efficient tool providing enhanced accuracy and broader applicability in simulating the complex interplay of interactions between ions and biomolecules, pivotal for improving our understanding of many biological processes.

biophysics↗

bioRxiv2023

The Sec61/TRAP Translocon Scrambles Lipids

Cell growth relies on the rapid flip-flop of newly synthesized lipids across the ER membrane. This process is facilitated without the need for ATP by specific membrane proteins--scramblases--a few of which have been very recently identified in the ER. We have previously resolved the structure of the translocon-associated protein (TRAP) bound to the Sec61 translocon in the ER membrane, and found this complex to render the membrane locally thinner. Moreover, Sec61 and TRAP each contain a crevice rich in polar residues that can shield a lipid head group as it traverses the hydrophobic membrane environment. We thus hypothesized that both Sec61 and TRAP act as ER scramblases. Here, we characterized the scrambling activity of Sec61 and TRAP using extensive molecular dynamics simulations. We observed that both Sec61 and TRAP efficiently scramble lipids via a credit card mechanism. We analyzed the kinetics and thermodynamics of lipid scrambling and demonstrated that local membrane thinning provides a key contribution to scrambling efficiency. Both proteins appear seemingly selective towards phosphatidylcholine lipids over phosphatidylethanolamine and phosphatidylserine, yet this behavior rather reflects the trends observed for these lipids in a protein-free membrane. The identified scrambling pathway in Sec61 structure is physiologically rarely unoccupied due to its role in protein translocation. Furthermore, we found that the scrambling activity of this pathway might be impeded by the presence of ions at a physiological concentration. However, the trimeric bundle of TRAP{beta}, TRAP{gamma}, and TRAP{delta} might provide scrambling activity insensitive to the functional state of the translocon and the solvent conditions.

biophysics↗

bioRxiv2023

Efficient Simulations of Membrane and Solvent Asymmetry With Flat-Bottom Restraints

The routinely employed periodic boundary conditions complicate molecular simulations of physiologically relevant asymmetric lipid membranes together with their distinct solvent environments. Therefore, separating the extracellular fluid from its cytosolic counterpart has often been performed using a costly double-bilayer setup. Here, we demonstrate that the lipid membrane and solvent asymmetry can be efficiently modeled with a single lipid bilayer by applying a flat-bottom potential to ions and other solute molecules, thereby restraining them to only interact with its relevant leaflet. We carefully optimized the parameters of the suggested method so that the results obtained using the flat-bottom and double-bilayer approaches become mutually indistinguishable. Then, we apply the flat-bottom approach to lipid bilayers with various compositions and solvent environments, covering ions and cationic peptides to validate the approach in a realistic use case. We also discuss the possible limitations of the method as well as its computational efficiency and provide a step-by-step guide on how to set up such simulations in a straightforward manner.

biophysics↗

bioRxiv2023

A Stealthy Player in Lipid Experiments? EDTA Binding to Phosphatidylcholine Membranes Probed by Simulations and Monolayer Experiments

Ethylenediaminetetraacetic acid (EDTA) is frequently used in lipid experiments to remove redundant ions, such as Ca2+, from the sample solution. In this work, combining molecular dynamics (MD) simulations and Langmuir monolayer experiments, we show that on top of the expected Ca2+ depletion, EDTA anions themselves bind to phosphatidylcholine (PC) monolayers. This binding, originating from EDTA interaction with choline groups of PC lipids, leads to the adsorption of EDTA anions at the monolayer surface and concentrationdependent changes in surface pressure as measured by monolayer experiments and explained by MD simulations. This surprising observation emphasizes that lipid experiments carried out using EDTA-containing solutions, especially of high concentrations, must be interpreted very carefully due to potential interfering interactions of EDTA with lipids and other biomolecules involved in the experiment, e.g., cationic peptides, that may alter membranebinding affinities of studied compounds. TOC Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/532294v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@128c201org.highwire.dtl.DTLVardef@d8eaeborg.highwire.dtl.DTLVardef@126edd0org.highwire.dtl.DTLVardef@c6f868_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗