Biology subjects

Borges-Araujo, L.

Publications and source records attributed to Borges-Araujo, L..

5 recordsLinked to original sources

bioRxiv2026

Towards transferable explicit-solvent coarse-grained models for biomolecular condensates

Biomolecular condensates formed by intrinsically disordered proteins require molecular models that accurately describe proteins in both dilute solution and condensed phases. Explicit-solvent coarse-grained models offer an attractive balance between chemical resolution and computational efficiency. Yet, it remains unclear whether improving dilute-state properties is sufficient to obtain an accurate description of condensates. Here, we address this question by introducing minimal modifications to the Martini 3 force field that combine recent advances in bonded interactions with refined protein-water interactions and strengthened glycine self-interactions, while preserving the underlying chemical transferability of the model. The resulting model substantially improves the description of single-chain conformations across a diverse benchmark of disordered proteins. We then investigate phase separation of the well-characterized low-complexity domain of heterogeneous nuclear ribonucleoprotein A1 and its sequence variants. The model reproduces several key physicochemical properties of biomolecular condensates, including chain expansion in the dense phase, sequence-dependent intermolecular contacts, protein diffusion and its relation to single-chain dimensions, and hydration, while revealing quantitative limitations in condensate density, phase equilibria, and ion partitioning. Our results show that improving dilute-state behaviour translates into a better description of condensed-phase properties, including condensate density, but is not sufficient to quantitatively reproduce the equilibrium between the dilute and dense phases.

biophysics↗

bioRxiv2026

Community Web Portal for Open Collaboration in the Martini Force Field Initiative

AO_SCPLOWBSTRACTC_SCPLOWThe Martini coarse-grained force field is widely used for biomolecular simulations by a large and rapidly expanding community worldwide. Over time, the development of Martini parameters, tools, and documentation has become increasingly dispersed across numerous research groups, leading to fragmentation and making it challenging for users and developers to keep track of the latest models, software, and best practices. Consequently, the development of Martini as a genuinely community-driven process has grown into a bottleneck. In response, the Martini Force Field Initiative (MFFI) has been established as an open-science effort to coordinate and support the collaborative development of all Martini resources. Here, we introduce the MFFI web portal, a platform designed around five core pillars: (i) avoiding reliance on a single group or local server; (ii) minimizing long-term maintenance overhead; (iii) reducing technical barriers for contributions; (iv) providing a unified home for parameters, tools, tutorials, example workflows, and research outputs; and (v) enabling timely dissemination of updates to the community. To achieve this, we use Quarto to generate a static website authored in Markdown, lowering the technical barrier to making contributions, and serverless architectures on Amazon Web Services for scalable, event-triggered backend operations. The source code is hosted in a public GitHub repository under an MIT license, with automated deployment via GitHub Actions and a contribution model based on pull requests for quality control. This design creates a sustainable, low-maintenance, and collaborative infrastructure that consolidates Martini resources and supports transparency. More broadly, our design exemplifies a transferable pattern for building open, community-oriented platforms for molecular modeling and computational science.

biophysics↗

bioRxiv2025

A Membrane-Disruptive Action of VBIT-4 Challenges Its Role as a Widely Used VDAC Oligomerization Inhibitor

Voltage-dependent anion channel (VDAC) is the most abundant protein of the mitochondrial outer membrane and a key regulator of metabolite exchange and mitochondrial physiology. Its oligomerization has been proposed to control processes such as mitochondrial DNA release and membrane remodeling, yet the underlying mechanisms remain poorly defined. VBIT-4 has been widely used over the last decade as a putative inhibitor of VDAC1 oligomerization, despite limited mechanistic validation. Here, using high-speed atomic force microscopy (AFM), we directly visualized VDAC1 assemblies in lipid membranes and examined the effect of VBIT-4. Unexpectedly, VBIT-4 induced membrane defects and permeabilization at micromolar concentrations, independently of VDAC1. Quantitative AFM analysis further shows that VBIT-4 does not alter VDAC1 cluster organization. Complementary electrophysiology, microscale thermophoresis, and coarse-grained molecular dynamics demonstrate that VBIT-4 partitions into lipid bilayers, increases membrane permeability, and destabilizes membrane structure, without detectable effects on VDAC1 channel properties or assemblies. Consistent with this mechanism, VBIT-4 induces VDAC1-independent cytotoxicity in HeLa cells at concentrations above 10 {micro}M. Together, these results demonstrate that VBIT-4 does not act as a specific inhibitor of VDAC1 oligomerization but instead functions as a membrane-active compound. This work provides a revised framework for interpreting studies using VBIT-4 and highlights the importance of systematically assessing drug-membrane interactions when targeting membrane proteins.

biochemistry↗

bioRxiv2025

Martini 3 protein models - a practical introduction to different structure bias models and their comparison

Biophysical characterization of protein structure and dynamics is essential in many scientific fields, including molecular biology, drug discovery, and enzyme design. Molecular dynamics (MD) simulations have become an increasingly important tool for studying these properties. This chapter provides a hands-on introduction to protein modeling with the Martini 3 coarse-grained (CG) force field. We outline its two-layer framework, where the first layer defines molecular topology and interactions, while the second layer applies structural bias to maintain secondary, tertiary, and quaternary structures. Three structure bias approaches - Elastic Network (EN), G[o]Martini, and OLIVES - are discussed, highlighting their advantages and trade-offs. Using a protein kinase as a case study, we demonstrate the step-by-step setup of Martini 3 protein models for simulations with the program package GROMACS, including system preparation, fine-tuning, and validation against atomistic reference simulations. Additionally, we explore the combination of an intrinsically disordered region (IDR) with a structured protein domain. By the end of this chapter, readers will have the necessary expertise to apply Martini 3-based protein modeling to a wide range of research applications.

biophysics↗

bioRxiv2021

SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 5 million people and is causing a devastating social and economic impact all over the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss vaccine and natural immunity, and increased transmissibility. All circulating VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes, via its receptor binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2). In an attempt to understand the effect of RBD mutations in circulating VOCs, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis is limited, since it ignores more indirect effects, such as the conformational dynamics of the RBD itself. Observing that some VOCs mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect RBD conformational dynamics. To test this, we performed long atomistic (AA) molecular dynamics (MD) simulations to investigate the structural dynamics of wt RBD, and that of three circulating VOCs (alpha, beta, and delta). Our results show that in solution, wt RBD presents two distinct conformations: an "open" conformation where it is free to bind ACE2; and a "closed" conformation, where the RBM ridge blocks the binding surface. The alpha and beta variants significantly impact the open/closed equilibrium, shifting it towards the open conformation by roughly 20%. This shift likely increases ACE2 binding affinity. Simulations of the currently predominant delta variant RBD were extreme in this regard, in that a closed conformation was never observed. Instead, the system alternated between the before mentioned open conformation and an alternative "reversed" one, with a significantly changed orientation of the RBM ridge flanking the RBD. This alternate conformation could potentially provide a fitness advantage not only due to increased availability for ACE2 binding, but also by aiding antibody escape through epitope occlusion. These results support the hypothesis that VOCs, and particularly the delta variant, impact RBD conformational dynamics in a direction that simultaneously promotes efficient binding to ACE2 and antibody escape.

biophysics↗