A5060523169- Protein Structure and Dynamics
- Enzyme Structure and Function
- Advanced NMR Techniques and Applications
- Spectroscopy and Quantum Chemical Studies
- Molecular spectroscopy and chirality
- Electron Spin Resonance Studies
- Advanced Proteomics Techniques and Applications
- Cancer, Hypoxia, and Metabolism
- Prion Diseases and Protein Misfolding
- RNA and protein synthesis mechanisms
- Force Microscopy Techniques and Applications
- Lipid Membrane Structure and Behavior
- NMR spectroscopy and applications
- Mass Spectrometry Techniques and Applications
- Advanced MRI Techniques and Applications
- Gene Regulatory Network Analysis
- Protein Kinase Regulation and GTPase Signaling
- Metabolomics and Mass Spectrometry Studies
- Computational Drug Discovery Methods
- Trace Elements in Health
- Endoplasmic Reticulum Stress and Disease
- Biotin and Related Studies
- Supramolecular Self-Assembly in Materials
- Photosynthetic Processes and Mechanisms
- Heavy metals in environment
University of Copenhagen
2020-2023
University of Trento
2017-2021
Istituto Nazionale di Fisica Nucleare, Trento Institute for Fundamental Physics And Applications
2016-2019
Polytechnic University of Turin
2019
Prions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie isoform (PrPSc) cellular (PrPC), caused epidemic and epizootic episodes [1]. Most aggregates other misfolding-prone proteins amyloids, often arranged a Parallel-In-Register-β-Sheet (PIRIBS) [2] or β-solenoid conformations [3]. Similar folding models have also been proposed for PrPSc, although none these confirmed experimentally....
Abstract Recent computational advancements in the simulation of biochemical processes allow investigating mechanisms involved protein regulation with realistic physics-based models, at an atomistic level resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on rationale negatively regulating levels targeting folding intermediates. Here, PPI-FIT was tested for first time...
Proteins display a wealth of dynamical motions that can be probed using both experiments and simulations. We present an approach to integrate side-chain NMR relaxation measurements with molecular dynamics simulations study the structure these motions. The approach, which we term ABSURDer (average block selection data entropy restraints), used find set trajectories are in agreement measurements. apply method deuterium T4 lysozyme show how it accuracy models protein afforded by fitting dynamic...
Circular dichroism (CD) is known to be an excellent tool for the determination of protein secondary structure due fingerprint signatures α and β domains. However, CD spectra are also sensitive 3D arrangement chain as a result excitonic nature additional signals aromatic residues. This double sensitivity, when extended time-resolved experiments, should allow folding monitored with high spatial resolution. To date, exploitation this very appealing idea has been limited, difficulty in relating...
Transition Path Theory (TPT) provides a rigorous framework to investigate the dynamics of rare thermally activated transitions. In this theory, central role is played by forward committor function q+(x), which ideal reaction coordinate. Furthermore, reactive and kinetics are fully characterized in terms two time-independent scalar vector distributions. work, we develop scheme enables all these ingredients TPT be efficiently computed using short non-equilibrium trajectories generated means...
We present an approach to optimize force field parameters using time-dependent data from NMR relaxation experiments. To do so, we scan in the dihedral angle potential energy terms describing rotation of methyl groups proteins and compare rates calculated molecular dynamics simulations with modified fields deuterium measurements T4 lysozyme. find that a small modification Cγ improves agreement experiments both for protein used when validating CI2 ubiquitin. also show these improvements enable...
Renormalization Group (RG) theory provides the theoretical framework to define rigorous effective theories, i.e., systematic low-resolution approximations of arbitrary microscopic models. Markov state models are shown be theories for Molecular Dynamics (MD). Based on this fact, we use real space RG vary resolution stochastic model and an algorithm clustering microstates into macrostates. The result is a lower dimensional which, by construction, optimal coarse-grained Markovian representation...
Nanodiscs based on membrane scaffold proteins (MSPs) and phospholipids are used as mimics to stabilize in solution for structural functional studies. Combining small-angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), time-resolved neutron (TR-SANS), we characterized the structure lipid bilayer properties of five different nanodiscs made with dimyristoylphosphatidylcholine MSPs varying size, charge, circularization. Our SAXS modeling showed that parameters embedded lipids...
We introduce an iterative algorithm to efficiently simulate protein folding and other conformational transitions, using state-of-the-art all-atom force fields. Starting from the Langevin equation, we obtain a self-consistent stochastic equation of motion, which directly yields reaction pathways. From solution this set equations derive estimate coordinate. validate approach against results plain MD simulations small protein, were performed on Anton supercomputer. In order explore...
The conformational heterogeneity of a folded protein can affect not only its function but also stability and folding. We recently discovered characterized stabilized double mutant (L49I/I57V) the CI2 showed that state-of-the-art prediction methods could predict increased relative to wild-type protein. Here, we have examined whether changed native-state dynamics, resulting entropy changes, explain changes in protein, as well two single forms. combined NMR relaxation measurements ps-ns...
Abstract Proteins display a wealth of dynamical motions that can be probed using both experiments and simulations. We present an approach to integrate side chain NMR relaxation measurements with molecular dynamics simulations study the structure these motions. The approach, which we term ABSURDer (Average Block Selection Using Relaxation Data Entropy Restraints) used find set trajectories are in agreement measurements. apply method deuterium T4 lysozyme, show how it accuracy models protein...
New software, called Marbles , is introduced that employs SAXS intensities to predict the shape of membrane proteins embedded into nanodiscs. To gain computational speed and efficient convergence, strategy based on a hybrid approach allows one account for contribution nanodisc intensity through semi-analytical model, while protein treated as set beads, similarly in well known ab initio methods. The reliability flexibility this proved by benchmarking code, implemented C++ with Python...
ABSTRACT Recent computational advancements in the simulation of biochemical processes allow investigating mechanisms involved protein regulation with realistic physics-based models, at an atomistic level resolution. Using these techniques to study negative androgen receptor (AR), we discovered a key functional role played by non-native metastable states appearing along folding pathway this protein. This unexpected observation inspired us design completely novel drug discovery approach, named...
The Bias Functional (BF) approach is a variational method which enables one to efficiently generate ensembles of reactive trajectories for complex biomolecular transitions, using ordinary computer clusters. For example, this scheme was applied simulate in atomistic detail the folding proteins consisting several hundreds amino acids and with experimental time minutes. A drawback BF that it produces do not satisfy microscopic reversibility. Consequently, cannot be used directly compute...
Abstract We present an approach to optimise force field parameters using time-dependent data from NMR relaxation experiments. To do so, we scan in the dihedral angle potential energy terms describing rotation of methyl groups proteins, and compare rates calculated molecular dynamics simulations with modified fields deuterium measurements T4 lysozyme. find that a small modification C γ improves agreement experiments both for protein used optimize field, when validating CI2 ubiquitin. also...
We introduce a powerful iterative algorithm to compute protein folding pathways, with realistic all-atom force fields. Using the path integral formalism, we explicitly derive modified Langevin equation which samples directly ensemble of reactive exponentially reducing cost simulating thermally activated transitions. The also yields rigorous stochastic estimate reaction coordinate. After illustrating this approach on simple toy model, successfully validate it against results ultra-long plain...
Abstract Prions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie isoform (PrP Sc ) cellular C ), is only one known to cause epidemic and epizootic episodes(1). Most aggregates other misfolding-prone proteins amyloids, often arranged a Parallel-In-Register-β-Sheet (PIRIBS)(2) or β-solenoid conformations(3). Similar folding models have also been proposed for PrP , although none these...
Molecular simulations and biophysical experiments can be used to provide independent complementary insights into the molecular origin of biological processes. A particularly useful strategy is use as a modelling tool interpret experimental measurements, data refine our models. Thus, explicit integration synergy between fundamental for furthering understanding This especially true in case where discrepancies measured simulated observables emerge. In this chapter, we an overview some core...