2025/04/06 by Josef Šulc, Jiřı́ Vondrášek · 1 voice
Biochemistry, Genetics and Molecular Biology · Materials Science · #Enzyme Structure and Function #Protein Structure and Dynamics #RNA and protein synthesis mechanisms
paper · pdf · doi:10.1021/acs.jpcb.4c04194
openalex publication_date 2025/04/06 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
This study explores the thermodynamic and structural behaviors of linker peptides, short polypeptide segments that often bridge protein domains. We are focusing on three prototypical classes─glycine-serine (GS), glycine-glycine (GG), and alanine-proline (AP)─and exploring their conformational dynamics as isolated entities outside a multidomain protein context. Using extensive molecular dynamics (MD) simulations and free energy perturbation (FEP) analyses, we characterize the free energy landscapes, entropic properties, and solvation energetics of 20 representative linkers. Our results reveal a pronounced linear relationship between linker length and key thermodynamic contributions, including zero-point vibrational energy (ZPVE), potential energy, and entropy. Notably, vibrational entropy emerges as a dominant stabilizing term. We also found that AP linkers display more rigid, yet extended conformations compared to the highly flexible GS and moderately flexible GG linkers. These findings underscore the nuanced role of linker composition in contributing to multidomain protein architecture and dynamics, and highlight how thermodynamic forces shape linker conformational behavior. Collectively, our work enhances the mechanistic understanding of protein linkers, offering valuable insights for the rational design of peptide-based systems and informing future efforts to modulate interdomain flexibility and stability in multidomain proteins.