Structural and Functional Annotation of Bioinorganic Systems: Perspectives and Challenges from Theory and Experiments
This workshop focuses on different aspects metal-dependent biology:
1. Metal-ion trafficking, transport, folding.
Regulatory proteins maintain an optimal available concentration and correct compartmentalization of biologically essential metal-ions as small concentration variation or metal-mislocation result to be toxic or may lead to diseases (neurodegenerative, cancer). Several metal-transporters, regulating metals intracellular uptake and/or efflux, and directing their trafficking inside the cell, have been identified. Moreover, metals play a key-role in modulating protein/nucleic acids stability and/or folding.
2. From traditional drugs to innovative targets.
Metal-ions are commonly used for diagnostic and therapeutic purposes. Understanding how metallo-drugs interfere with metal-sensing pathways as well as their interactomic network is crucial to identify their biological targets/off-targets responsible of effects/side-effects, yet this information is mostly lacking.
Novel targets based on transition metals are being identified. A typical example is iron-sulfur proteins: well known for a wide-range of essential biological processes (respiration, photosynthesis, nitrogen fixation or sensing of iron or oxygen, substrate binding/catalysis and gene expression regulation). These proteins have been recently emerged as potentially associated with Parkinson’s disease and to be involved in cancer and diabetes, along with metabolic, genetic and biogenesis-related diseases.
3. Biomolecular engineering
Metallo-proteins or metal-dependent RNA filaments perform/enhance the efficiency of specific chemical reactions exploiting the electronic properties of metals. A detailed mechanistic understanding of these processes aims at engineering natural biological systems for bio-technological applications or to the design of small molecules (drugs) to interfere with them.
An ever-increasing quantitative characterization of the above mentioned metal-dependent biological processed is aimed to be obtained by computer simulations and will be discussed.
Transition metal-based biomolecular properties critically depend on their electronic structure. QM/MM methods rely most often on Density Functional Theory (DFT) for the QM region because of its favorable scaling with number of atoms and its reasonable accuracy. DFT generally fails with strongly-correlated systems, which can be accounted accurately only by multi-configuration methods. These are extremely computationally-expensive and rarely applied to biological molecules. Extensive research has been dedicated to test and improve the performance of DFT when dealing with transition metals systems. DFT failures typically have only modest impact on the structural features of biomolecules, but they can tremendously affect their kinetic, thermodynamics and spectroscopic properties both in the ground and excited-states.
The computational cost of the QM calculations limits QM/MM MD to reach time-scales orders of magnitude smaller that those required by interesting biological phenomena. Enhanced-sampling techniques can be applied if the computational interest is restricted to a limited portion of the biomolecule and this portion does not vary in time. All other situations (metal-dependent folding, metal-transport) pose theoretical challenges and advances are urged to reveal their essential features.
Paolo Carloni ( German Research School for Simulation Sciences Julich ) - Organiser
Rachel Nechushtai ( Hebrew University of Jerusalem, Israel ) - Organiser
Vincenzo Barone ( Scuola Normale Superiore ) - Organiser
Giuseppe Brancato ( Scuola Normale Superiore, Pisa ) - Organiser
Giuseppe Legname ( Scuola Internazionale Superiore di Studi Avanzati, Trieste ) - Organiser & speaker
Alessandra Magistrato ( CNR-IOM@SISSA ) - Organiser