Temperature Replica-Exchange Molecular Dynamics Reveals a Heterogeneous Recognition-Compatible Ensemble of the Laminin-Derived Peptide CDPGYIGSR

The laminin-derived nonapeptide CDPGYIGSR contains the bioactive YIGSR motif, historically associated with inhibition of tumor cell adhesion, invasion, angiogenesis, and laminin-receptor-mediated cell responses. Although these activities have often been attributed to the 37/67 kDa laminin receptor/RPSA axis, the molecular identity and organization of the laminin-binding receptor system remain debated. This uncertainty makes it essential to define the intrinsic conformational preferences of CDPGYIGSR in solution before assigning a unique receptor-bound structure. In this study, temperature replica-exchange molecular dynamics (T-REMD) simulations in explicit solvent are employed to characterize the solution conformational ensemble of CDPGYIGSR. Free energy landscape analysis, clustering, and structural descriptors reveal a predominant compact bend-like backbone arrangement, together with alternative low-lying conformational states within a heterogeneous ensemble. Rather than assuming a single bioactive conformation, the conformational ensemble is analyzed in terms of structural features that are consistent with available NMR observations and reported structure–activity relationships. Importantly, the most populated conformations in solution do not necessarily correspond to the bioactive state upon receptor binding. Instead, a subset of conformations sharing common structural motifs, including a central backbone bend and specific residue exposure patterns, may represent states compatible with receptor recognition. These results provide an ensemble-based structural framework that connects simulation-derived conformational motifs with available NMR observations and structure–activity data, supporting a recognition-compatible ensemble model in which compact preorganized states may contribute to receptor binding.