Atomic Detail of Protein Folding Revealed by an Ab Initio Reappraisal of Circular Dichroism

Ianeselli, Alan; Orioli, Simone; Spagnolli, Giovanni; Faccioli, P.; Cupellini, Lorenzo; Jurinovich, Sandro; Mennucci, Benedetta

doi:10.1021/jacs.7b12399

Cited by 42 publications

(47 citation statements)

References 76 publications

(141 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, whenever a reasonable proxy of the RC is available, then the BF variational scheme enables to keep the systematic errors of rMD to a minimum. Protein folding pathways obtained with the BF approach have been found to agree very well with the results of both plain MD simulations [13] and kinetic experiments [17,18], arguably reflecting the fact that a good RC for these is available [19], supported also by energy landscape theory arguments [20]. Unfortunately, the BF approach may be flawed by uncontrolled systematic errors when applied to study processes in which the RC is poorly known.…”

Section: Introductionmentioning

confidence: 58%

All-Atom Simulation of the HET-s Prion Replication

Spagnolli²,

Boldrini

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Prions are self-replicative protein particles lacking nucleic acids. Originally discovered for causing infectious neurodegenerative disorders, they have also been found to play several physiological roles in a variety of species. Functional and pathogenic prions share a common mechanism of replication, characterized by the ability of an amyloid conformer to propagate by inducing the conversion of its physiological, soluble counterpart. In this work, we focus on the propagation of the prion forming domain of HET-s, a physiological fungal prion for which high-resolution structural data are available. Since time-resolved biophysical experiments cannot yield a full reconstruction of prion replication, we resort to computational methods. To overcome the computational limitations of plain Molecular Dynamics (MD) simulations, we adopt a special type of biased dynamics called ratchet-and-pawl MD (rMD). The accuracy of this enhanced path sampling protocol strongly depends on the choice of the collective variable (CV) used to define the biasing force. Since for prion propagation a reliable reaction coordinate (RC) is not yet available, we resort to the recently developed Self-Consistent Path Sampling (SCPS). Indeed, in such an approach the CV where the biasing force is applied is not heuristically postulated but is calculated through an iterative refinement procedure. Our atomistic reconstruction of the HET-s replication shows remarkable similarities with a previously reported mechanism of mammalian PrP Sc propagation obtained with a different computational protocol. Together, these results indicate that the propagation of prions generated by evolutionary distant proteins shares common features. In particular, in both these cases, prions propagate their conformation through a very similar templating mechanism.

show abstract

Section: Introductionmentioning

confidence: 58%

All-Atom Simulation of the HET-s Prion Replication

Spagnolli²,

Boldrini

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In order to bridge the gap between the computationallyaccessible and the biologically-relevant time scales, we employed a specific kind of biased dynamics called ratchet-and-pawl MD (rMD) (15) in the framework of an all-atom realistic force field (16). rMD-based methods have been successfully applied to simulate protein folding and other conformational transitions (17,18). However, this scheme provides a sampling of the transition path ensemble only if the biasing force is applied along a reliable reaction coordinate (19).…”

Section: Resultsmentioning

confidence: 99%

Full Atomistic Model of Prion Structure and Conversion

Spagnolli

Rigoli

Orioli

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

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 ) of the cellular prion protein (PrP C ), is the only one known to cause epidemic and epizootic episodes(1). Most aggregates of other misfolding-prone proteins are amyloids, often arranged in a Parallel-In-Register-β-Sheet (PIRIBS)(2) or βsolenoid conformations(3). Similar folding models have also been proposed for PrP Sc , although none of these have been confirmed experimentally. Recent cryo-electron microscopy (cryo-EM) and X-ray fiberdiffraction studies provided evidence that PrP Sc is structured as a 4-rung β-solenoid (4RβS)(4, 5). Here, we combined different experimental data and computational techniques to build the first physically-plausible, atomic resolution model of mouse PrP Sc , based on the 4RβS architecture. The stability of this new PrP Sc model, as assessed by Molecular Dynamics (MD) simulations, was found to be comparable to that of the prion forming domain of Het-s, a naturally-occurring β-solenoid. Importantly, the 4RβS arrangement allowed the first simulation of the sequence of events underlying PrP C conversion into PrP Sc . Our results provide the most updated, experimentally-driven and physically-coherent model of PrP Sc , together with an unprecedented reconstruction of the mechanism underlying the self-catalytic propagation of prions. SignificanceSince the original hypothesis by Stanley Prusiner, prions have represented enigmatic agents diverging from the classical concept of genetic inheritance. However, the structure of PrP Sc , the infectious isoform of the cellular prion protein (PrP C ), has so far remained elusive, mostly due to technical challenges posed by its aggregation propensity. Here, we present a new high resolution model of PrP Sc derived from the integration of a wide array of recent experimental constraints. By coupling the information of such model with a newly developed computational method, we reconstructed for the first time the conformational transition of PrP C to PrP Sc . This study offers a unique workbench for designing therapeutics against prion diseases, and a physically-plausible mechanism explaining how protein conformation could self-propagate.

show abstract

“…For these reasons, the forward model can be of high complexity (e.g. quantum calculations can be carried out on the ensemble structures [94]). This is not the case, however, of experimentbiased simulations: when implemented within a molecular simulation, forward models are evaluated and differentiated at (almost) every step, so they have to be sufficiently simple to assure computational efficiency [43] and their gradients have to be known analytically.…”

Section: Forward Modelsmentioning

confidence: 99%

How to learn from inconsistencies: Integrating molecular simulations with experimental data

Orioli

Larsen

Bottaro

et al. 2020

Progress in Molecular Biology and Translational Science

Self Cite

167

View full text Add to dashboard Cite

Molecular simulations and biophysical experiments can be used to provide independent and complementary insights into the molecular origin of biological processes. A particularly useful strategy is to use molecular simulations as a modelling tool to interpret experimental measurements, and to use experimental data to refine our biophysical models. Thus, explicit integration and synergy between molecular simulations and experiments is fundamental for furthering our understanding of biological processes. This is especially true in the case where discrepancies between measured and simulated observables emerge. In this chapter, we provide an overview of some of the core ideas behind methods that were developed to improve the consistency between experimental information and numerical predictions. We distinguish between situations where experiments are used to refine our understanding and models of specific systems, and situations where experiments are used more generally to refine transferable models. We discuss different philosophies and attempt to unify them in a single framework. Until now, such integration between experiments and simulations have mostly been applied to static data, and we discuss more recent developments aimed to analyse time-dependent or time-resolved data.

show abstract

Atomic Detail of Protein Folding Revealed by an Ab Initio Reappraisal of Circular Dichroism

Cited by 42 publications

References 76 publications

All-Atom Simulation of the HET-s Prion Replication

All-Atom Simulation of the HET-s Prion Replication

Full Atomistic Model of Prion Structure and Conversion

How to learn from inconsistencies: Integrating molecular simulations with experimental data

Contact Info

Product

Resources

About