Entropy-enthalpy interplay in aluminum bound neurofilaments

Considerable amount of work has been shown to understand the preferred chelation modes of metal-binding peptides using quantum mechanical calculations, resulting in a hierarchy of binding affinities. Previous work has shown an increasing stabilization energy for higher coordination complexes. However, as the coordination of a metal increases, the conformational space available for the polypeptide chain is inevitably reduced. Resolving the many entropic contributions from different degrees of freedom is particularly challenging. In this work, we explore this problem focusing on a family of phosphorylated neuropeptides that bind to aluminum. Determination of the configurational entropy is done using Maximum Information Spanning Tree (MIST) scheme implemented in the parallel software PARENT. We find that there is a general negative correlation between both stabilization energy and entropy, and that a subtle interplay determines the population of the most favorable species, rewarding a balance between both contributions. Additionally, we synthesize and discuss the requirements for a possible Metal Ion Hypothesis based on our findings.