Folding Thermodynamics and Pathway Heterogeneity of Lanmodulin from Atomistic Simulations
Abstract
ABSTRACT: Lanmodulin (LanM), a metal-binding EF-hand protein, is widely believed to fold into its functional conformation only upon coordination with rare earth elements such as lanthanide ions. Here, we challenge this assumption through advanced atomistic molecular dynamics simulations that combine parallel tempering and well-tempered metadynamics to probe the thermodynamics and folding pathways of LanM under apo conditions. By mapping the folding free energy landscape, identifying unfolded, misfolded and folded basins, and integrating contact map analysis, reactive folding trajectory analysis and diffusion map-based dimensionality reduction, we discover a striking deviation from canonical models: LanM spontaneously adopts a native-like fold, including structured EF-hand motifs and a well-formed hydrophobic core, even in the absence of metal ions. We find that the LanM folding mechanism proceeds via a two-step pathway – initial entropically driven collapse into a metastable misfolded ensemble that retain partial or full helices but in misaligned arrangements, followed by an enthalpically favorable reorganization into the folded state. Folding trajectories and diffusion map-based embeddings further reveal and distinguishes pathway multiplicity: some transitions proceed directly from the unfolded to the folded state, while others transiently occupy the misfolded basin, underscoring kinetic heterogeneity and misfolded basin’s role as an accessible but non-obligate…
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