Rodgers, Nicole; Lalaurie, Christophe; McDonnell, Thomas; (2025) Simulation of the trimeric globular head of C1q reveals temperature-sensitive network: implications for inflammation. Journal of Molecular Modeling , 31 , Article 247. 10.1007/s00894-025-06464-y.

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Abstract

CONTEXT: C1q is an important protein in immune processes, driving complement activation through the classical pathway. Further to this, alterations in C1q either through SNPs or through autoantibodies can lead to systemic lupus erythematosus. Beyond these functions, C1q can also bind to other inflammatory proteins such as C-reactive protein (CRP) via its globular domain, when CRP is in the pentameric form. These interactions require specific structures to facilitate binding. Using molecular dynamics simulations, it is possible to measure the movements of proteins over time, with increasing temperatures allowing them to explore most of their available conformational space. Here, we describe using an increasing temperature simulation of C1q to identify potential structures generated during states of increased energy such as inflammation. Increasing temperature yielded significantly more movement of the monomeric and trimeric protein forms. Monomer A drove most movement within the molecule regardless of temperature, within the monomer and trimer. Further to this, novel structures were generated at higher temperatures, with significant movement of the CRP binding site. The altered movement in the CRP binding amino acids was correlative with increased temperature driving a loss of correlation between the different amino acids involved. Increased temperature and energy in the system leads to an alteration of C1q’s structure, which may leave it unable to bind to CRP in solution. This could have implications for the activity of the C1q/CRP complex as well as both proteins individually. METHODS: Models were generated using PDB:1PK6 and prepared using Charmm-GUI’s online platform. Protein simulations were run using NAMD on the UCL HPC facility (ARC). Trajectories were combined and aligned for analysis and visualised using Visual Molecular Dynamics (VMD). Analysis was carried out using VMD, R Studio, and Excel to identify novel structures of C1q, areas of increased flexibility, and potential protein networks.

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