2021
DOI: 10.1021/acsphyschemau.1c00039
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Binding Energy and Free Energy of Calcium Ion to Calmodulin EF-Hands with the Drude Polarizable Force Field

Abstract: Calcium ions are important messenger molecules in cells, which bind calcium-binding proteins to trigger many biochemical processes. We constructed four model systems, each containing one EF-hand loop of calmodulin with one calcium ion bound, and investigated the binding energy and free energy of Ca2+ by the quantum mechanics symmetry-adapted perturbation theory (SAPT) method and the molecular mechanics with the additive CHARMM36m (C36m) and the polarizable Drude force fields (FFs). Our results show that the ex… Show more

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Cited by 16 publications
(20 citation statements)
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“…Parameters for all atoms within the simulation were determined from the Charmm36 force field . Although previous studies have detailed difficulties of modeling Ca 2+ ion interactions and Ca 2+ -binding free energies in MD simulations involving biomolecules, the Charmm36 force field has been shown as a reliable force field option for producing experimental-like configurations of proteins in simulations where Ca 2+ is bound to an EF-hand protein (i.e., troponin) . The TMD simulations were conducted using an NPT ensemble at 310 K with Langevin temperature and pressure dampening.…”
Section: Methodsmentioning
confidence: 99%
“…Parameters for all atoms within the simulation were determined from the Charmm36 force field . Although previous studies have detailed difficulties of modeling Ca 2+ ion interactions and Ca 2+ -binding free energies in MD simulations involving biomolecules, the Charmm36 force field has been shown as a reliable force field option for producing experimental-like configurations of proteins in simulations where Ca 2+ is bound to an EF-hand protein (i.e., troponin) . The TMD simulations were conducted using an NPT ensemble at 310 K with Langevin temperature and pressure dampening.…”
Section: Methodsmentioning
confidence: 99%
“…Calmodulin (CaM) is a regulatory Ca 2+ -binding protein involved in the regulation of many important biological processes. [43][44][45] The calcium-binding motif in CaM is a helix-loop-helix structure named EF-hand comprising 12 residues. The binding of calcium ions causes the conformation transition of EF-hand loops and induces substantial rearrangement.…”
Section: Modeling Systemsmentioning
confidence: 99%
“…The binding of calcium ions causes the conformation transition of EF-hand loops and induces substantial rearrangement. 43,45 EF-loops I to IV of CaM comprise residue numbers 20-31, 56-67, 93-104, and 129-140, respectively. Many studies have been conducted to determine the binding affinity and selectivity of four EF-hand loops, experimentally and computationally.…”
mentioning
confidence: 99%
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“…Among the other techniques for the BFE calculations, techniques including the free energy perturbation method, thermodynamic integration, and umbrella sampling have been used for rigorous estimates of Ca 2+ affinity for a variety of CBPs. However, results are often not consistent with experimental findings. The prediction of the correct order of binding of Ca 2+ to different proteins is even more challenging. Recent work, which describes the impact of troponin C mutations on calcium binding affinity using adaptive steered molecular dynamics, illustrates this point.…”
Section: Introductionmentioning
confidence: 99%