Carboxylate-Rich Disordered Peptide as Selective Nanomolar Chelator for Cu²⁺: A Theoretical Analysis

The heptapeptide KGKDDED features a C-terminal acidic cluster (D⁴–D⁷) that serves as a high-affinity binding motif for divalent metal ions through carboxylate coordination. Using a combination of bioinorganic principles Hard-Soft Acid-Base theory, ionic radii, charge density analysis, and empirical structural data we present a comprehensive theoretical investigation of its interactions with Li⁺, Ni²⁺, Co²⁺, Cu²⁺, and Pb²⁺. Our predictions indicate that Cu²⁺ forms the most stable and structurally well-defined complex, characterized by square-planar coordination to D⁵, E⁶, and D⁷, low backbone RMSD (1.60 Å), high coordination persistence (96%), and a predicted dissociation constant (Kd) of ~10⁻⁸ M. Ni²⁺ and Co²⁺ also bind strongly in octahedral geometries involving all four carboxylates, while Pb²⁺ exhibits irregular, hemi directed coordination due to its stereo chemically active 6s² lone pair. In contrast, Li⁺ shows negligible binding under physiological conditions. Energy decomposition analysis reveals that binding is driven overwhelmingly by electrostatics, partially offset by a substantial desolvation penalty. Notably, metal binding reduces the intrinsic disorder of KGKDDED, with Cu²⁺ inducing the greatest conformational stabilization. These findings position of KGKDDED as a promising scaffold for Cu²⁺-selective biosensors, antimicrobial adjuvants, or probes for copper dyshomeostasis in neurodegenerative diseases. The study underscores the capacity of short, His-free, carboxylate-rich peptides to achieve selective transition metal recognition through geometric and electrostatic complementarity.