RESUMO
In the last several years, there has been a surge in the development of machine learning potential (MLP) models for describing molecular systems. We are interested in a particular area of this field - the training of system-specific MLPs for reactive systems - with the goal of using these MLPs to accelerate free energy simulations of chemical and enzyme reactions. To help new members in our labs become familiar with the basic techniques, we have put together a self-guided Colab tutorial (https://cc-ats.github.io/mlp_tutorial/), which we expect to be also useful to other young researchers in the community. Our tutorial begins with the introduction of simple feedforward neural network (FNN) and kernel-based (using Gaussian process regression, GPR) models by fitting the two-dimensional Müller-Brown potential. Subsequently, two simple descriptors are presented for extracting features of molecular systems: symmetry functions (including the ANI variant) and embedding neural networks (such as DeepPot-SE). Lastly, these features will be fed into FNN and GPR models to reproduce the energies and forces for the molecular configurations in a Claisen rearrangement reaction.
RESUMO
Parkinson's disease is accompanied by the presence of amyloids in the brain that are formed of α-synuclein chains. The correlation between COVID-19 and the onset of Parkinson's disease led to the idea that amyloidogenic segments in SARS-COV-2 proteins can induce aggregation of α-synuclein. Using molecular dynamic simulations, we show that the fragment FKNIDGYFKI of the spike protein, which is unique for SARS-COV-2, preferentially shifts the ensemble of α-synuclein monomer toward rod-like fibril seeding conformations and, at the same time, differentially stabilizes this polymorph over the competing twister-like structure. Our results are compared with earlier work relying on a different protein fragment that is not specific for SARS-COV-2.
Assuntos
Doença de Parkinson , Glicoproteína da Espícula de Coronavírus , alfa-Sinucleína , Humanos , alfa-Sinucleína/química , Amiloide/química , Doença de Parkinson/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/químicaRESUMO
Background: Amyloidosis is a major long-term complication of chronic disease; however, whether it represents one of the complications of post-myocardial infarction (MI) is yet to be fully understood. Methods: Using wild-type and knocked-out MI mouse models and characterizing in vitro the exosomal communication between bone marrow-derived macrophages and activated mesenchymal stromal cells (MSC) isolated after MI, we investigated the mechanism behind Serum Amyloid A 3 (SAA3) protein overproduction in injured hearts. Results: Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived SAA3 monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from a subset of activated MSC, which, in response to MI, acquire the expression of a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin (PDPN). Cardiac MSC PDPN+ communicate with and activate macrophages through their extracellular vesicles or exosomes. Specifically, MSC PDPN+ derived exosomes (MSC PDPN+ Exosomes) are enriched in SAA3 and exosomal SAA3 protein engages with Toll-like receptor 2 (TRL2) on macrophages, triggering an overproduction and impaired clearance of SAA3 proteins, resulting in aggregation of SAA3 monomers as rigid amyloid deposits in the extracellular space. The onset of amyloid fibers deposition alongside extra-cellular-matrix (ECM) proteins in the ischemic heart exacerbates the rigidity and stiffness of the scar, hindering the contractility of viable myocardium and overall impairing organ function. Using SAA3 and TLR2 deficient mouse models, we show that SAA3 delivered by MSC PDPN+ exosomes promotes post-MI amyloidosis. Inhibition of SAA3 aggregation via administration of a retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils, positively modulates the scar formation, and improves heart function post-MI. Conclusion: Overall, our findings provide mechanistic insights into post-MI amyloidosis and suggest that SAA3 may be an attractive target for effective scar reversal after ischemic injury and a potential target in multiple diseases characterized by a similar pattern of inflammation and amyloid deposition. NOVELTY AND SIGNIFICANCE: What is known? Accumulation of rigid amyloid structures in the left ventricular wall impairs ventricle contractility.After myocardial infarction cardiac Mesenchymal Stromal Cells (MSC) acquire Podoplanin (PDPN) to better interact with immune cells.Amyloid structures can accumulate in the heart after chronic inflammatory conditions. What information does this article contribute? Whether accumulation of cumbersome amyloid structures in the ischemic scar impairs left ventricle contractility, and scar reversal after myocardial infarction (MI) has never been investigated.The pathophysiological relevance of PDPN acquirement by MSC and the functional role of their secreted exosomes in the context of post-MI cardiac remodeling has not been investigated.Amyloid structures are present in the scar after ischemia and are composed of macrophage-derived Serum Amyloid A (SAA) 3 monomers, although mechanisms of SAA3 overproduction is not established. SUMMARY OF NOVELTY AND SIGNIFICANCE: Here, we report that amyloidosis, a secondary phenomenon of an already preexisting and prolonged chronic inflammatory condition, occurs after MI and that amyloid structures are composed of macrophage-derived SAA3 monomers. Frequently studied cardiac amyloidosis are caused by aggregation of immunoglobulin light chains, transthyretin, fibrinogen, and apolipoprotein in a healthy heart as a consequence of systemic chronic inflammation leading to congestive heart failure with various types of arrhythmias and tissue stiffness. Although chronic MI is considered a systemic inflammatory condition, studies regarding the possible accumulation of amyloidogenic proteins after MI and the mechanisms involved in that process are yet to be reported. Here, we show that SAA3 overproduction in macrophages is triggered in a Toll-like Receptor 2 (TLR2)-p38MAP Kinase-dependent manner by exosomal communication from a subset of activated MSC, which, in response to MI, express a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin. We provide the full mechanism of this phenomenon in murine models and confirm SAA3 amyloidosis in failing human heart samples. Moreover, we developed a retro-inverso D-peptide therapeutic approach, "DRI-R5S," specifically designed to bind SAA3 monomers and prevent post-MI aggregation and deposition of SAA3 amyloid fibrils without interfering with the innate immune response.
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Covid-19 can lead to the onset of type-II diabetes which is associated with aggregation of islet amyloid polypeptides, also called amylin. Using molecular dynamics simulations, we investigate how the equilibrium, between amylin monomers in its functional form and fibrils associated with diabetes, is altered in presence of SARS-COV-2 protein fragments. For this purpose, we study the interaction between the fragment SFYVYSRVK of the Envelope protein or the fragment FKNIDGYFKI of the Spike protein with the monomer and two amylin fibril models. Our results are compared with earlier work studying such interactions for two different proteins.
RESUMO
COVID-19 can lead to the onset of type-II diabetes, which is associated with the aggregation of islet amyloid polypeptides, also called amylin. Using molecular dynamics simulations, we investigate how the equilibrium between amylin monomers in its functional form and fibrils associated with diabetes is altered in the presence of SARS-COV-2 protein fragments. For this purpose, we study the interaction between the fragment SFYVYSRVK of the envelope protein or the fragment FKNIDGYFKI of the spike protein with the monomer and two amylin fibril models. Our results are compared with earlier work studying such interactions for the two different proteins.
RESUMO
Parkinson's Disease is accompanied by presence of amyloids in the brain formed of α-synuclein chains. Correlation between COVID-19 and the onset of Parkinson's disease let to the idea that amyloidogenic segments in SARS-COV-2 proteins can induce aggregation of α-synuclein. Using molecular dynamic simulations, we show that the fragment FKNIDGYFKI of the spike protein, which is unique for SARS-COV-2, shifts preferentially the ensemble of α-synuclein monomer towards rod-like fibril seeding conformations, and at the same time stabilizes differentially this polymorph over the competing twister-like structure. Our results are compared with earlier work relying on a different protein fragment that is not specific for SARS-COV-2.
RESUMO
Using molecular dynamic simulations we study whether amyloidogenic regions in viral proteins can initiate and modulate formation of α-synuclein aggregates, thought to be the disease-causing agent in Parkinson's Disease. As an example we choose the nine-residue fragment SFYVYSRVK (SK9), located on the C-terminal of the Envelope protein of SARS-COV-2. We probe how the presence of SK9 affects the conformational ensemble of α-synuclein monomers and the stability of two resolved fibril polymorphs. We find that the viral protein fragment SK9 may alter α-synuclein amyloid formation by shifting the ensemble toward aggregation-prone and preferentially rod-like fibril seeding conformations. However, SK9 has only little effect of the stability of pre-existing or newly-formed fibrils.
RESUMO
Aggregates of α-synuclein are thought to be the disease-causing agent in Parkinson's disease. Various case studies have hinted at a correlation between COVID-19 and the onset of Parkinson's disease. For this reason, we use molecular dynamics simulations to study whether amyloidogenic regions in SARS-COV-2 proteins can initiate and modulate aggregation of α-synuclein. As an example, we choose the nine-residue fragment SFYVYSRVK (SK9), located on the C-terminal of the envelope protein of SARS-COV-2. We probe how the presence of SK9 affects the conformational ensemble of α-synuclein monomers and the stability of two resolved fibril polymorphs. We find that the viral protein fragment SK9 may alter α-synuclein amyloid formation by shifting the ensemble toward aggregation-prone and preferentially rod-like fibril seeding conformations. However, SK9 has only a small effect on the stability of pre-existing or newly formed fibrils. A potential mechanism and key residues for potential virus-induced amyloid formation are described.