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Abstract:
Advances in structural biology, particularly cryo-electron microscopy, have enabled high-resolution characterization of complex protein assemblies. These developments underscore the need for computational approaches capable of describing biologically relevant conformational changes over extended timescales. GōMartini 3 is a coarse-grained approach that demonstrates computational efficiency and versatility across several systems, from membrane-binding proteins and soluble proteins to intrinsically disordered proteins, while preserving key physicochemical features. In this work, we introduce an optimized approach that integrates dynamic contact information from all-atom molecular dynamics (AA-MD) simulations to refine the contact map in GōMartini simulations and select the AA-MD structure consistent with the refined map. Specifically, we define high-frequency contacts, which reduce the number of original Gō contact set by ≈20%–30%, thereby improving the representation of conformational states beyond the original approach in Martini 3. Benchmarking different contact selection criteria revealed that including intra- and interchain high-frequency contacts in protein assemblies captures structural flexibility and domain dynamics. The method was tested on single-chain globular proteins and on the SARS-CoV-2 spike protein. Overall, the optimized contact map improves sampling efficiency and expands the accessible conformational landscape. The full framework is available as an open-source tool for large-scale simulations of protein assemblies.

Keywords:
GōMartini 3 , Molecular Simulation, Proteins, Biomolecular Ensemble, Free Energy, Coarse-graining, cryo-electron microscopy

Abstract:
The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is the main target of neutralizing antibodies (Abs) and nanobodies (Nbs). Although their binding affinities are well characterized, their mechanical stability under force remains poorly understood, despite its relevance in viral attachment, immune recognition, and receptor engagement. Here, we present a comparative nanomechanical analysis of three Abs (PDI-231, S2X259, and R1-32) and three Nbs (R14, C1, and n3113.1) bound to the RBD from the WT and Omicron variants BA.4 and JN.1. Using steered molecular dynamics within the Martini 3 coarse-grained framework, we identified distinct mechanical signatures determined by epitope topology, binding architecture, and variant-specific mutations. Ab/RBD complexes display asymmetric rupture events in which the heavy chain serves as the main pathway for force transmission, while the light chain provides secondary reinforcement. The cooperative action of both chains enhances mechanical resilience, supporting rupture forces near 500 pN. In contrast, Nb/RBD complexes exhibit rigid-body dissociation with direct force transmission through compact single-domain scaffolds and minimal structural deformation. Variant-dependent unfolding of RBD regions, particularly residues 438–507 and 516–529, appears as a recurrent fracture motif contributing to adaptive mechanical response. These results establish mechanical stability as a key descriptor of immune complex robustness, complementing thermodynamic affinity. By linking architecture, epitope geometry, and force propagation, this study provides a quantitative framework for designing antibodies and nanobodies with improved mechanical resilience against viral evolution.

Abstract:
Coarse-grained modeling has become an important tool to supplement experimental measurements, allowing access to spatio-temporal scales beyond all-atom based approaches. The GōMartini model combines structure- and physics-based coarse-grained approaches, balancing computational efficiency and accurate representation of protein dynamics with the capabilities of studying proteins in different biological environments. This paper introduces an enhanced GōMartini model, which combines a virtual-site implementation of Gō models with Martini 3. The implementation has been extensively tested by the community since the release of the reparametrized version of Martini. This work demonstrates the capabilities of the model in diverse case studies, ranging from protein-membrane binding to protein-ligand interactions and AFM force profile calculations. The model is also versatile, as it can address recent inaccuracies reported in the Martini protein model. Lastly, the paper discusses the advantages, limitations, and future perspectives of the Martini 3 protein model and its combination with Gō models.

Keywords:
GōMartini 3, Martini 3, Coarse graining, Proteins, IDP, membranes, Molecular Dynamics, Nanomechanics

Abstract:
Rational design of novel antibody therapeutics against viral infections such as coronavirus relies on surface complementarity and high affinity for their effectiveness. Here, we explore an additional property of protein complexes, the intrinsic mechanical stability, in SARS-CoV-2 variants when complexed with a potent antibody. In this study, we utilized a recent implementation of the GōMartini 3 approach to investigate large conformational changes in protein complexes with a focus on the mechanostability of the receptor-binding domain (RBD) from WT, Alpha, Delta, and XBB.1.5 variants in complex with the H11-H4 nanobody. The analysis revealed moderate differences in mechanical stability among these variants. Also, we identified crucial residues in both the RBD and certain protein segments in the nanobody that contribute to this property. By performing pulling simulations and monitoring the presence of specific native and non-native contacts across the protein complex interface, we provided mechanistic insights into the dissociation process. Force-displacement profiles indicate a tensile force clamp mechanism associated with the type of protein complex. Our computational approach not only highlights the key mechanostable interactions that are necessary to maintain overall stability, but it also paves the way for the rational design of potent antibodies that are mechanostable and effective against emergent SARS-CoV-2 variants.

Keywords:
SARS-CoV-2, GōMartini 3, Nanomechanics, Protein complexes, protein engineering, MD, native contacts