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Molecular dynamics free energy simulations of ATP:Mg²⁺ and ADP:Mg²⁺ using the polarizable force field AMOEBA.

ABSTRACT: ATPases and GTPases are two important classes of protein that play critical roles in energy transduction, cellular signaling, gene regulation and catalysis. These proteins use cofactors such as nucleoside di and tri-phosphates (NTP, NDP) and can detect the difference between NDP and NTP which then induce different protein conformations. Mechanisms that drive proteins into the NTP or NDP conformation may depend on factors such as ligand structure and how Mg²⁺ coordinates with the ligand, amino acids in the pocket and water molecules. Here, we have used the advanced electrostatic and polarizable force field AMOEBA and molecular dynamics free energy simulations (MDFE) to examine the various binding mechanisms of ATP:Mg²⁺ and ADP:Mg²⁺.We compared the ATP:Mg²⁺ binding with previous studies using non-polarizable force fields and experimental data on the binding affinity. It was found that the total free energy of binding for ATP:Mg²⁺ (-7.00 ± 2.13 kcal/mol) is in good agreement with experimental values (-8.6 ± .2 kcal/mol)¹. In addition, parameters for relevant protonation states of ATP, ADP, GTP and GDP have been derived. These parameters will allow for researchers to investigate biochemical phenomena involving NTP's and NDP's with greater accuracy than previous studies involving non-polarizable force fields.

SUBMITTER: Walker B

PROVIDER: S-EPMC8375395 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The hydration free energy, structure, and dynamics of the zinc divalent cation are studied using a polarizable force field in molecular dynamics simulations. Parameters for the Zn(2+) are derived from gas-phase ab initio calculation of Zn(2+)-water dimer. The Thole-based dipole polarization is adjusted based on the Constrained Space Orbital Variations (CSOV) calculation while the Symmetry Adapted Perturbation Theory (SAPT) approach is also discussed. The vdW parameters of Zn(2+) have been obtained by comparing the AMOEBA Zn(2+)-water dimerization energy with results from several theory levels and basis sets over a range of distances. Molecular dynamics simulations of Zn(2+) solvation in bulk water are subsequently performed with the polarizable force field. The calculated first-shell water coordination number, water residence time and free energy of hydration are consistent with experimental and previous theoretical values. The study is supplemented with extensive Reduced Variational Space (RVS) and Electron Localization Function (ELF) computations in order to unravel the nature of the bonding in Zn(2+)(H(2)O)(n) (n=1,6) complexes and to analyze the charge transfer contribution to the complexes. Results show that the importance of charge transfer decreases as the size of Zn-water cluster grows due to anticooperativity and to changes in the nature of the metal-ligand bonds. Induction could be dominated by polarization when the system approaches condensed-phase and the covelant effects are eliminated from the Zn(II)-water interaction. To construct an "effective" classical polarizable potential for Zn(2+) in bulk water, one should therefore avoid over-fitting to the ab initio charge transfer energy of Zn(2+)-water dimer. Indeed, in order to avoid overestimation of condensed-phase many-body effects, which is crucial to the transferability of polarizable molecular dynamics, charge transfer should not be included within the classical polarization contribution and should preferably be either incorporated in to the pairwise van der Waals contribution or treated explicitly.

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Molecular dynamics free energy simulations of ATP:Mg²⁺ and ADP:Mg²⁺ using the polarizable force field AMOEBA.

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Dataset Information

Molecular dynamics free energy simulations of ATP:Mg2+ and ADP:Mg2+ using the polarizable force field AMOEBA.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Molecular dynamics free energy simulations of ATP:Mg²⁺ and ADP:Mg²⁺ using the polarizable force field AMOEBA.