Multiscale simulation of molecular processes in cellular environments

Chiricotto, Mara; Sterpone, Fabio; Derreumaux, Philippe; Melchionna, Simone

doi:10.1098/rsta.2016.0225

Cited by 22 publications

(30 citation statements)

References 60 publications

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“…Simulations can provide valuable insights into monomerdependent secondary nucleation by testing its requirements in terms of molecular nature and interaction potentials and may elucidate possible molecular events and driving forces. A number of Monte Carlo or molecular dynamics simulations have used various levels of coarse graining [38][39][40][154][155][156][157][158] or atomistic representation, 100,101,159 as recently reviewed, 160 and provide insights into the energy barriers and transitions during primary nucleation. However, large system size and simulation time are required to capture both fibril formation and the subsequent secondary nucleation step.…”

Section: Insights From Simulationsmentioning

confidence: 99%

Secondary nucleation in amyloid formation

et al. 2018

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Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates. A key question in current research is the molecular mechanism and driving forces governing such processes, known as secondary nucleation. In this context, the analogies with other self-assembling systems for which monomer-dependent secondary nucleation has been studied for more than a century provide a valuable source of inspiration. Here, we present a short overview of this background and then review recent results regarding secondary nucleation of amyloid-forming peptides and proteins, focusing in particular on the amyloid β peptide (Aβ) from Alzheimer's disease, with some examples regarding α-synuclein from Parkinson's disease. Monomer-dependent secondary nucleation of Aβ was discovered using a combination of kinetic experiments, global analysis, seeding experiments and selective isotope-enrichment, which pinpoint the monomer as the origin of new aggregates in a fibril-catalyzed reaction. Insights into driving forces are gained from variations of solution conditions, temperature and peptide sequence. Selective inhibition of secondary nucleation is explored as an effective means to limit oligomer production and toxicity. We also review experiments aimed at finding interaction partners of oligomers generated by secondary nucleation in an ongoing aggregation process. At the end of this feature article we bring forward outstanding questions and testable mechanistic hypotheses regarding monomer-dependent secondary nucleation in amyloid formation.

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Section: Insights From Simulationsmentioning

confidence: 99%

Secondary nucleation in amyloid formation

et al. 2018

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“…Such models can at least at a general qualitative level capture the main features of biomolecular structure and dynamics cellular environments. 149,168,169 Atomistic simulations, with explicit 26,143,170−176 or implicit solvent, 27,97,98 or multiscale models, where atomistic and coarse-grained resolutions are mixed, 169 provide even greater levels of detail and can, at least in principle, satisfy all of the requirements for modeling crowded cellular environments outlined above. However, because the balance between molecular stability, weak interactions, and solvent interactions in crowded environments depends on subtle shifts between enthalpic and entropic energy terms, the major challenge is an accurate interaction potential, both at the coarse-grained and atomistic level that can accurately reproduce both intra- and intermolecular interactions.…”

Section: Cellular Environments In Computer Simulationsmentioning

confidence: 99%

Crowding in Cellular Environments at an Atomistic Level from Computer Simulations

et al. 2017

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The effects of crowding in biological environments on biomolecular structure, dynamics, and function remain not well understood. Computer simulations of atomistic models of concentrated peptide and protein systems at different levels of complexity are beginning to provide new insights. Crowding, weak interactions with other macromolecules and metabolites, and altered solvent properties within cellular environments appear to remodel the energy landscape of peptides and proteins in significant ways including the possibility of native state destabilization. Crowding is also seen to affect dynamic properties, both conformational dynamics and diffusional properties of macromolecules. Recent simulations that address these questions are reviewed here and discussed in the context of relevant experiments.

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“…With the Exascale capability at our doorsteps, LB can be taken to the next level: from the study of basic biofluidic processes to the direct simulation of full-scale cellular compartments, like protein cargoes, vesicles and possibly even full-scale organelles. The endeavor commands the integration of the LBPD paradigm within a broad scope software infrastructures, including mechanical models of biological structures, ranging from all-atom molecules to elastic networks for membranes and so forth [209].…”

Section: Direct Simulation Of Full-scale Cell Compartments: Golgi mentioning

confidence: 99%

Mesoscopic simulations at the physics-chemistry-biology interface

Bernaschi¹,

Melchionna²,

Succi

2019

Rev. Mod. Phys.

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We discuss the Lattice Boltzmann-Particle Dynamics (LBPD) multiscale paradigm for the simulation of complex states of flowing matter at the interface between Physics, Chemistry and Biology.In particular, we describe current large-scale LBPD simulations of biopolymer translocation across cellular membranes, molecular transport in ion channels and amyloid aggregation in cells. We also provide prospects for future LBPD explorations in the direction of cellular organization, the direct simulation of full biological organelles, all the way to up to physiological scales of potential relevance to future precision-medicine applications, such as the accurate description of homeostatic processes.It is argued that, with the advent of Exascale computing, the mesoscale physics approach advocated in this paper, may come to age in the next decade and open up new exciting perspectives for physics-based computational medicine.

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Multiscale simulation of molecular processes in cellular environments

Cited by 22 publications

References 60 publications

Secondary nucleation in amyloid formation

Secondary nucleation in amyloid formation

Crowding in Cellular Environments at an Atomistic Level from Computer Simulations

Mesoscopic simulations at the physics-chemistry-biology interface

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