Biology subjects

Riopedre-Fernandez, M.

Publications and source records attributed to Riopedre-Fernandez, M..

4 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

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

Can calmodulin bind to lipids of the cytosolic leaflet of plasma membranes?

Calmodulin (CaM) is a ubiquitous calcium-sensitive messenger in eukaryotic cells. It was previously shown that CaM possesses an affinity for diverse lipid moieties, including those found on CaM-binding proteins. These facts together with our observation that CaM accumulates in membrane-rich protrusions of HeLa cells upon increased cytosolic calcium, motivated us to perform a systematic search for unmediated CaM interactions with model lipid membranes mimicking the cytosolic leaflet of plasma membranes. A range of experimental techniques and Molecular Dynamics simulations proves unambiguously that CaM interacts with lipid bilayers in the presence of calcium ions. Lipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) hold the key to CaM-membrane interactions. Calcium induces an essential conformational rearrangement of CaM, but its binding to the headgroup of PS also neutralizes the membrane negative surface charge. More intriguingly, PE plays a dual role - it forms hydrogen bonds with CaM, but also destabilizes the lipid bilayer to increase exposure of hydrophobic acyl chains to the interacting proteins. Our findings suggest that upon increased intracellular calcium concentration, CaM and the cytosolic leaflet of cellular membranes can be functionally connected.

biophysics↗