Charge scaling, also denoted as the electronic continuum correction, has proven to be an efficient method for effectively including electronic polarization in force field molecular dynamics simulations without additional computational costs. However, scaling charges in existing force fields, fitted at least in part to experimental data, lead to inconsistencies, such as overscaling. We have, therefore, recently developed a four-site water model consistent with charge scaling, i.e., possessing the correct low-frequency dielectric constant of 45. Here, we build on top of this water model to develop charge-scaled models of biologically relevant Li+, Na+, K+, Ca2+, and Mg2+ cations as well as Cl-, Br-, and I- anions, employing machine learning to streamline and speed up the parametrization process. On the one hand, we show that the present model outperforms the best existing charge scaled model of aqueous ions. On the other hand, the present work points to a future need for consistently and simultaneously improving the water and ion models within the electronic continuum correction framework.

• Publikační typ
• časopisecké články MeSH

We designed a minimalistic zinc(II)-binding peptide featuring the Cys2His2 zinc-finger motif. To this aim, several tens of thousands of (His/Cys)-Xn-(His/Cys) protein fragments (n=2-20) were first extracted from the 3D protein structures deposited in Protein Data Bank (PDB). Based on geometrical constraints positioning two Cys (C) and two His (H) side chains at the vertices of a tetrahedron, approximately 22 000 sequences of the (H/C)-Xi-(H/C)-Xj-(H/C)-Xk-(H/C) type, satisfying Nmetal-binding H=Nmetal-binding C=2, were processed. Several other criteria, such as the secondary structure content and predicted fold stability, were then used to select the best candidates. To prove the viability of the computational design experimentally, three peptides were synthesized and subjected to isothermal calorimetry (ITC) measurements to determine the binding constants with Zn2+, including the entropy and enthalpy terms. For the strongest Zn2+ ions binding peptide, P1, the dissociation constant was shown to be in the nanomolar range (KD=~220 nM; corresponding to ΔGbind=-9.1 kcal mol-1). In addition, ITC showed that the [P1 : Zn2+] complex forms in 1 : 1 stoichiometry and two protons are released upon binding, which suggests that the zinc coordination involves both cysteines. NMR experiments also indicated that the structure of the [P1 : Zn2+] complex might be quite similar to the computationally predicted one. In summary, our proof-of-principle study highlights the usefulness of our computational protocol for designing novel metal-binding peptides.

• Klíčová slova
• Computer design, Isothermal calorimetry, Metal-binding peptide, NMR, QM modeling, Zinc(II),
• MeSH
• molekulární modely MeSH
• peptidy * chemie   metabolismus   chemická syntéza   MeSH
• sekvence aminokyselin MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• zinek * chemie   metabolismus   MeSH
• zinkové prsty MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• peptidy * MeSH
• zinek * MeSH

prosECCo75 is an optimized force field effectively incorporating electronic polarization via charge scaling. It aims to enhance the accuracy of nominally nonpolarizable molecular dynamics simulations for interactions in biologically relevant systems involving water, ions, proteins, lipids, and saccharides. Recognizing the inherent limitations of nonpolarizable force fields in precisely modeling electrostatic interactions essential for various biological processes, we mitigate these shortcomings by accounting for electronic polarizability in a physically rigorous mean-field way that does not add to computational costs. With this scaling of (both integer and partial) charges within the CHARMM36 framework, prosECCo75 addresses overbinding artifacts. This improves agreement with experimental ion binding data across a broad spectrum of systems─lipid membranes, proteins (including peptides and amino acids), and saccharides─without compromising their biomolecular structures. prosECCo75 thus emerges as a computationally efficient tool providing enhanced accuracy and broader applicability in simulating the complex interplay of interactions between ions and biomolecules, pivotal for improving our understanding of many biological processes.

• MeSH
• peptidy chemie   MeSH
• proteiny chemie   MeSH
• simulace molekulární dynamiky * MeSH
• statická elektřina * MeSH
• voda chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• peptidy MeSH
• proteiny MeSH
• voda MeSH

We employed density functional theory-based ab initio molecular dynamics simulations to examine the hydration structure of several common alkali and alkali earth metal cations. We found that the commonly used atom pairwise dispersion correction scheme D3, which assigns dispersion coefficients based on the neutral form of the atom rather than its actual oxidation state, leads to inaccuracies in the hydration structures of these cations. We evaluated this effect for lithium, sodium, potassium, and calcium and found that the inaccuracies are particularly pronounced for sodium and potassium compared to the experiment. To remedy this issue, we propose disabling the D3 correction specifically for all cation-including pairs, which leads to a much better agreement with experimental data.

• Publikační typ
• časopisecké články MeSH

Non-local analogues of Auger decay are increasingly recognized as important relaxation processes in the condensed phase. Here, we explore non-local autoionization, specifically Intermolecular Coulombic Decay (ICD), of a series of aqueous-phase isoelectronic cations following 1s core-level ionization. In particular, we focus on Na+, Mg2+, and Al3+ ions. We unambiguously identify the ICD contribution to the K-edge Auger spectrum. The different strength of the ion-water interactions is manifested by varying intensities of the respective signals: the ICD signal intensity is greatest for the Al3+ case, weaker for Mg2+, and absent for weakly-solvent-bound Na+. With the assistance of ab initio calculations and molecular dynamics simulations, we provide a microscopic understanding of the non-local decay processes. We assign the ICD signals to decay processes ending in two-hole states, delocalized between the central ion and neighbouring water. Importantly, these processes are shown to be highly selective with respect to the promoted water solvent ionization channels. Furthermore, using a core-hole-clock analysis, the associated ICD timescales are estimated to be around 76 fs for Mg2+ and 34 fs for Al3+. Building on these results, we argue that Auger and ICD spectroscopy represents a unique tool for the exploration of intra- and inter-molecular structure in the liquid phase, simultaneously providing both structural and electronic information.

• Publikační typ
• časopisecké články MeSH

The initial activation step in the gating of ubiquitously expressed Orai1 calcium (Ca2+) ion channels represents the activation of the Ca2+-sensor protein STIM1 upon Ca2+ store depletion of the endoplasmic reticulum. Previous studies using constitutively active Orai1 mutants gave rise to, but did not directly test, the hypothesis that STIM1-mediated Orai1 pore opening is accompanied by a global conformational change of all Orai transmembrane domain (TM) helices within the channel complex. We prove that a local conformational change spreads omnidirectionally within the Orai1 complex. Our results demonstrate that these locally induced global, opening-permissive TM motions are indispensable for pore opening and require clearance of a series of Orai1 gating checkpoints. We discovered these gating checkpoints in the middle and cytosolic extended TM domain regions. Our findings are based on a library of double point mutants that contain each one loss-of-function with one gain-of-function point mutation in a series of possible combinations. We demonstrated that an array of loss-of-function mutations are dominant over most gain-of-function mutations within the same as well as of an adjacent Orai subunit. We further identified inter- and intramolecular salt-bridge interactions of Orai subunits as a core element of an opening-permissive Orai channel architecture. Collectively, clearance and synergistic action of all these gating checkpoints are required to allow STIM1 coupling and Orai1 pore opening. Our results unravel novel insights in the preconditions of the unique fingerprint of CRAC channel activation, provide a valuable source for future structural resolutions, and help to understand the molecular basis of disease-causing mutations.

• Klíčová slova
• AND-gate, CRAC channel, Electrophysiology, Gating, Gating checkpoints, Opening-permissive conformation, Orai1, STIM1, Signal propagation,
• MeSH
• bakteriální proteiny genetika   metabolismus   MeSH
• fosfatidylcholiny chemie   metabolismus   MeSH
• gating iontového kanálu genetika   MeSH
• genetické vektory chemie   metabolismus   MeSH
• HEK293 buňky MeSH
• interakční proteinové domény a motivy MeSH
• konformace proteinů, alfa-helix MeSH
• konformace proteinů, beta-řetězec MeSH
• lidé MeSH
• liposomy chemie   metabolismus   MeSH
• luminescentní proteiny genetika   metabolismus   MeSH
• metoda terčíkového zámku MeSH
• mutace MeSH
• nádorové proteiny chemie   genetika   metabolismus   MeSH
• protein ORAI1 chemie   genetika   metabolismus   MeSH
• protein STIM1 chemie   genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• rekombinantní proteiny chemie   genetika   metabolismus   MeSH
• reportérové geny MeSH
• simulace molekulární dynamiky MeSH
• substituce aminokyselin MeSH
• vápník metabolismus   MeSH
• vápníková signalizace * MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-palmitoyl-2-oleoylphosphatidylcholine MeSH Prohlížeč
• bakteriální proteiny MeSH
• enhanced cyan fluorescent protein MeSH Prohlížeč
• fosfatidylcholiny MeSH
• liposomy MeSH
• luminescentní proteiny MeSH
• nádorové proteiny MeSH
• ORAI1 protein, human MeSH Prohlížeč
• protein ORAI1 MeSH
• protein STIM1 MeSH
• rekombinantní proteiny MeSH
• STIM1 protein, human MeSH Prohlížeč
• vápník MeSH
• yellow fluorescent protein, Bacteria MeSH Prohlížeč
• zelené fluorescenční proteiny MeSH