1) Facing the challenges of computing metals

We will open the discussion on the challenges of computing metals at the classical and Quantum Mechanical (QM) levels.
Each metal, with its own coordination geometry and electronic structure represents a challenge for molecular simulations, due to the limitations of the current FFs. We will focus on the development of site-specific force-field (FF) parameters, which is promising to overcome the limitations of current models.

On the QM side, high-level methods are able to describe multiconfigurational states, reproducing the correct spin multiplicity and estimating possible charge-delocalization, resulting useful in the case of transition metal complexes. Density Functional Theory (DFT) protocols (spin projections, spin flipping) and post-HF methods will be under intense debate in this workshop. Modeling metals considering their realistic biological environment fundamentally relies on the use of a quantum mechanics/molecular mechanics (QMMM) scheme. We will discuss the development of polarizable QMMM schemes that can help in dealing with problems such as the “spill- out” effect, arising from the unphysical interaction between the electronic density and the classical charge at the boundary between the QM and MM partitioning.

2) Metal ions and biological function.

Here, three major topics will be discussed:

Recognition and binding. We will focus on studies on metal ion recognition and binding in proteins and nucleic acids. We will deepen the role of computations in deciphering how protein conformational plasticity allows the selection of the metal ion, as well as on the mechanisms underlying the metal-aided catalysis.

Steric vs electronic effects. We will discuss the role of QM-methods in deciphering how steric and electronic effects affect enzymatic function. QM-methods can (i) discern steric and electronic effects of metals during catalysis; (ii) provide information on which metal is most efficient/selective into the enzyme pocket; (iii) explain the structural/electronic basis for different catalytic efficiency of “similar” metals (i.e. Mg, Ca, Zn or Mn) within enzymes.

Electron transfer. Charge transfer has particular relevance for processes such as respiration and photosynthesis. Metalloproteins are key players, being able to fine-tuning their redox potential, and providing natural binding centers for the moving electrons. We will discuss on the role of QM in providing critical information – usually out of reach via experiments – on redox properties and electron transfer processes.

3) Metal ions for drug discovery
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Recent advances in metal-based anticancer treatment have shown that combined computations and experiments allow characterizing the mechanism of action. We will discuss how QMMM schemes can be fully integrated with a variety of experiments, characterizing the action of metal centers at the level of proteins and DNA, elucidating the cytotoxicity mechanism and impact on cancer cell function.

4) Metal ions in material science.

QM calculations can predict electronic structure properties for the design of efficient materials. High accuracy in computations relies on the development of novel exchange correlation functionals including all relevant interactions, with attention to dispersion and spin-orbit coupling. All these points will be discussed in light of the applications for solar cell technology and next-generation batteries.

Physiological ions such as Na+, K+, Ca2+, Cl- carry electric current in the brain. However, their impact in neurobiology goes well beyond this already absolutely fundamental role. Indeed, physiological ions (including the above list and H+) play a key role for key neurobiological events such as receptor activation, ion channel gating, and the consequent signal cascades triggered by these receptors. These cascades involve protein/protein interactions,  enzymatic reactions, and, importantly, they may impact on neuronal epigenetics, hence on DNA binding to their target proteins in the nucleus.  Indeed, the strength of these interactions not only depends on the structure and dynamics of the proteins and the receptors, as very often successfully addressed by molecular simulation studies, but also on the dynamics of the surrounding ions, which interact in a subtle and complex manner with the biomolecules.  This aspect needs to be further clarified and it is less investigated by the molecular dynamics community. Therefore, characterizing the effect of ions on these enormously diverse biomolecular systems is crucial to elucidate the underlying mechanisms of neuronal function and dysfunction, i.e. in the presence of pathological conditions such as Alzheimer’s and schizophrenia.

The goal of the present workshop is to foster discussions between scientists from different communities. These include scientists developing and applying statistical mechanical and quantum chemical methods  - often dealing with accurate predictions of relative simple systems, such as ions in solutions, as well as biomolecular simulators, who have to deal with the enormous complexity of systems such as neurological receptors and ion channels, enzymes and nucleic acids binding to proteins. Here, many approximations and assumptions in the modeling of ions (such as the transferability of force fields parameters on different ionic strengths) are often accepted without validation. Direct communication and debate during and after the talks among scientists from different communities is a highly efficient way to challenge some of the commonly accepted approximations and lead to an overall improvement of the description of ions in neurobiological environments.

Selected topics to be covered during the Meeting include:

1. Molecular simulations of ligand-neuroreceptor interactions, neuroreceptor activation and ion permeation and gating of ion channels at different ionic strengths.

2. Multiscale simulations of ligand binding to metallo-proteins and metallo-enzyme mechanisms involved in neuronal cascades.

3. Role of ions for nucleic acids structure, dynamics and binding to their target proteins.

4. Development of accurate force fields for the treatment of ions in interaction with biomolecules.

5. Accurate description of ions in solutions, based on effective potentials and/or on quantum chemical methods.

6. Proton transfer phenomena in neuroreceptors.