Multi-Force-Field Molecular Dynamics Reveals How Cation Hydration Kinetics Dictate Polypeptide Assembly Pathways and Timescales.

Authors

Lei Bao, Ben-Chao Zhu, Chenjie Feng, Zhen Wang, Ying Liu

Published in

Journal of chemical theory and computation. Jul 09, 2026. Epub Jul 09, 2026.

Abstract

The distinct roles of Mg²⁺ and Ca²⁺ ions in biomolecular assembly can be understood through their different hydration dynamics, but a quantitative, causal link between the water-exchange kinetics of cations and assembly pathways has been lacking. Here, we establish this relationship using multi-force-field all-atom molecular dynamics simulations combined with enhanced sampling and Markov state model analysis. By systematically comparing force fields that inherently encode different hydration exchange rates, we show that the Mg²⁺ ion, with its kinetically inert hydration shell (microsecond water exchange), must undergo stepwise dehydration to coordinate aspartate residues. This kinetic barrier limits its ability to induce microphase separation on microsecond timescales, positioning the Mg²⁺ ion as a slow "structural reorganizer" that gradually disrupts preexisting Arg-Asp salt bridges. In contrast, the Ca²⁺ ion, with its rapidly exchanging hydration shell (picosecond-to-nanosecond water exchange), directly bridges multiple aspartate side-chains and acts as a fast "microphase separation trigger." Quantitative comparison of water-exchange rates across force fields, validated against experimental NMR data, establishes a causal chain from hydration kinetics to coordination modes to assembly timescales. Based on these results, we propose a "hydration clock" model in which the intrinsic water-exchange kinetics of cations dictates the fundamental timescales of biomolecular assembly. This work provides a kinetic framework, grounded in explicit-solvent molecular dynamics and multi-force-field validation, for understanding cation-specific effects and the rational design of time-programmable self-assembling systems.

PMID:
42424594
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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