Springer nature is developing a new tool to find and evaluate protocols. Computational approaches to understanding protein aggregation in. Computer simulation offers unique possibilities for investigating molecularlevel phenomena difficult to probe experimentally. In this work, we employed atomistic molecular dynamics md simulations to study the conformational dynamics of sod1barrel monomer in different concentrations of trifluoroethanol tfe.
Jul 19, 2018 molecular culprits of protein aggregation in als and ftld. In this paper, the second in a series devoted to molecular modeling of protein aggregation, a mesoscale model of proteins together with extensive discontinuous molecular dynamics simulation is. Molecular dynamics md simulations have emerged as a potent and predictive tool to study aggregation mechanisms at molecular levels. Specific attention is devoted to issues with implications for biotechnology. Further experiments immediately hinted at the importance of this protein interaction. Molecular dynamics md, which integrates directly newtons equation of motion, offers the most detailed. Previous experimental studies reported that dopamine prevented the formation of hiapp oligomers and fibrils. Cationic amino acid residues are bound by the synergistic effect of disperse, hydrophobic, and electrostatic interactions in a kinetically fast reversible process. Impact of sucrose level on storage stability of proteins. Molecular lysine tweezers counteract aberrant protein. Dynamics of an intrinsically disordered protein reveal.
Pdf probing protein aggregation using discrete molecular. Using a combination of fluorescence microscopy and electron tomography, peskett et al. Here we present molecular dynamics simulations aimed at investigating. Subsequent mechanistic investigations revealed how atpdependent dynamic protein aggregation regulates cellular dormancy and resuscitation, the fine control of which facilitates bacterial drug tolerance. Intrinsic disorder modulates protein selfassembly and aggregation. Aug 22, 2019 previous experimental studies reported that dopamine prevented the formation of hiapp oligomers and fibrils. Molecular dynamics simulations and bioinformatic analysis. Discrete molecular dynamics simulations of simplified protein models have emerged as a powerful methodology with its ability to bridge the gap in time and length scales from protein. It is worth noting that molecular dynamics simulations can only sample a time range of at most hundreds of nanoseconds and allatom simulations have therefore sampled only early events in aggregation. Probing protein aggregation using simplified models and. Computational methods for studying protein misfolding and aggregation. Jul 18, 2018 vib the flanders institute for biotechnology. Discrete molecular dynamics simulations of simplified protein models have emerged as a powerful methodology with its ability to bridge the gap in time and length scales from protein dynamics to aggregation, and provide an indispensable tool for probing protein aggregation.
Molecular dynamics studies of synthetic and biological. The central apo sod1 barrel was involved in protein maturation and. Probing the early stages of prion protein prp aggregation. Molecular aggregation is the cause of a wideranging variety of. Probing protein aggregation using simplified models and discrete. Molecular dynamics simulations reveal the inhibitory mechanism of dopamine against human islet amyloid polypeptide hiapp aggregation and its destabilization effect on hiapp protofibrils zenghui lao department of physics, state key laboratory of surface physics, key laboratory for computational physical sciences ministry of education, fudan university, 2005 songhu road, shanghai 200438, peoples republic of china. To speed up the occurrence of interesting events, a number of nonstandard approaches to molecular dynamics simulations have been adopted. Here we present molecular dynamics simulations aimed at investigating the aggregation process of the. Molecular culprits of protein aggregation in als and ftld. Thermodynamics of protein aggregation sciencedirect. Ultimately, the comparative analysis of the a 40 and a 42 aggregation kinetics is of interest. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. Pdf molecular dynamics simulation of protein biosurfactants.
We have measured reconfiguration of unfolded prion of two species under a variety of conditions and found a wide range of rates. These featuress make nmr a unique and powerful tool in studying protein dynamics related to protein functions, and there has been a tremendous growth in these applications since the. The full text of this article hosted at is unavailable due to technical difficulties. In this context, carefully planned molecular dynamics simulation studies, computations using coarsegrained models, and bioinformatic analysis have given considerable insights into the early events in. Pikal1 1department of pharmaceutical sciences, school of pharmacy, university of connecticut, storrs, connecticut 062693092. Pdf the 60s gave birth to the practical implementation of classical mechanics to unravel the dynamics and energetics of biomolecules.
We performed a series of molecular dynamics md simulations of bovine. Hongli liu, haiyang zhong, xuewei liu, shuangyan zhou, shuoyan tan, huanxiang liu, xiaojun yao. A molecular dynamics md simulation at a microsecond level was. Automated longitudinal monitoring of in vivo protein. A dualfunctional bodipybased molecular rotor probe reveals different viscosity of protein aggregates in live cells using fluorescence lifetime imaging, in revision. The monomeric inactive protein can be activated as discussed earlier and. Longterm protein aggregation analysis in a huntington disease hd c. Lysozyme comprises all secondary structure types and, as such, is well suited for such an analysis. Pdf multiscale molecular dynamics of protein aggregation. Prions are selfreplicating infectious proteinaceous agents whose conformations are capable of forming amyloidlike aggregate fibrils. By contrast, amyloidogenic protein sequences such as a. Automated markov state models for molecular dynamics. Drawing from a wealth of studies concerning protein folding, computational studies of protein aggregation are emerging.
Assessing the potential of atomistic molecular dynamics. The aggregated protein is transmissible to other organisms and species. Peptidebased inhibitors have gradually been implicated as drugs for treating protein folding diseases because of their favorable biocompatibility and low toxicity. Molecular lysine tweezers counteract aberrant protein aggregation.
These studies have been successful in capturing aspects. The aggregation was found to be a pointlineplane process. Jun 17, 20 to study the conformational changes of a. Computational models, especially when combined with experimental approaches, are increasingly useful for the. Correlation of aggregation rate with protein structure and molecular mobility bingquan wang,1 serguei tchessalov,2 marcus t. Molecular dynamics simulation of protein adsorption at. Discrete molecular dynamics simulations of simplified protein models have emerged as a powerful methodology with its ability to bridge the gap in time and length scales from protein dynamics to. Molecular dynamics md simulations were performed to provide molecular insight into the aggregation process of graphene oxide go in water. Herein we investigated the conformational ensembles of hiapp dimer with and without dopamine using replicaexchange molecular dynamics simulations. However, the underlying inhibitory mechanism at the atomic level remains elusive.
Protein aggregation occurs through several steps fig. Pdf ab initio discrete molecular dynamics approach to. In silico approaches to simulate amyloid aggregation. Dalbya,1 adepartment of biochemical engineering, university college london, london wc1h 0ah, united kingdom. These studies have been successful in capturing aspects of aggregation known from experiment and are being used to refine experimental methods aimed at abating aggregation. The monomeric inactive protein can be activated as discussed earlier and can lead to the formation of oligomers that can precipitate as insoluble amorphous aggregates or can nucleate into larger oligomers. Early events in aggregation of proteins are not easily accessible by experiments. Molecular dynamics study of the aggregation process of. A mathematical model of heat shock response to study the.
Macroscopic observables laboratory are related to microscopic behavior atomic level. Dynamics, at times coupled with the use of enhanced. Ab initio discrete molecular dynamics approach to protein folding and aggregation. Keyes, structure optimization and folding mechanisms of offlattice protein models using statistical temperature molecular dynamics simulation. Aggregation is believed to originate in cellular endosomes at low ph. Here, we describe progress along this direction using examples taken largely from our own work. Electrostatic unfolding and interactions of albumin driven. The central apo sod1 barrel was involved in protein maturation and pathological aggregation in als. Jul 18, 2018 one fus protein domain was generally considered to mediate aggregation, but the new findings indicate that arginine residues in another region of the protein are also required for maturation of fus in cellular stress granules. Ferrocenemodified peptides as inhibitors against insulin. Molecular simulation of protein aggregation bratko. The prion protein aggregates and causes neurodegenerative diseases in many mammalian species. Here we examine hypothesisdriven simplified protein models in conjunction with discrete molecular dynamics in the study of protein aggregation, implicated in series of neurodegenerative diseases. In this context, carefully planned molecular dynamics simulation studies, computations using coarsegrained models, and bioinformatic analysis have given considerable insights into the early events in the route to fibril formation.
The journal publishes original scientific research papers that provide. Molecular aggregation is the cause of a wideranging variety of diseases but can also play important functional roles in our body, and selfassembled nanostructures have many promising applications. Central idea of molecular dynamics simulations biological activity is the result of time dependent interactions between molecules and these interactions occur at the interfaces such as proteinprotein, proteinna, proteinligand. Impact of sucrose level on storage stability of proteins in. Advances in the simulation of protein aggregation at the atomistic. Molecular flexibility and hydrophobicitycharge interaction in amyloid peptides as studied by molecular dynamics simulations, proteins. Coupled molecular dynamics mediate long and shortrange epistasis between mutations that affect stability and aggregation kinetics haoran yua and paul a. Protein aggregation into highly structured amyloid fibrils is associated with various diseases. Journal of molecular biology jmb provides high quality, comprehensive and broad coverage in all areas of molecular biology. Disclosing the mechanism of spontaneous aggregation and. Molecular dynamics of proteins atpase, a molecular motor that synthesizes the bodys weight of atp a day a ternary complex of dna, lac repressor, and cap controlling gene expression aqp. Molecular simulation of protein aggregation request pdf. Studying the early stages of protein aggregation using.
Misfolding and aggregation of cu, zn superoxide dismutase sod1 is often found in amyotrophic lateral sclerosis als patients. Proteinprotein recognition and binding are governed by diffusion, noncovalent forces and conformational flexibility, entangled in a way that only molecular dynamics simulations can dissect at. To ascertain that this approach is not specific only for the als model, we monitor the dynamics of protein. Molecular dynamics is a twovolume compendium of the evergrowing applications of molecular dynamics simulations to solve a wider range of scientific and engineering challenges. Solvent sensitivity of protein aggregation in cu, zn. Molecular simulation of protein aggregation bratko 2007. Molecular dynamics driven design of phstabilized mutants. Apr 04, 2017 the prion protein aggregates and causes neurodegenerative diseases in many mammalian species. Spontaneous aggregation of fibrilforming peptides studied by. May 17, 2018 using a combination of fluorescence microscopy and electron tomography, peskett et al.
Mnei is a single chain derivative of monellin, a plant protein that can interact with the human sweet taste receptor, being therefore perceived as sweet. Eugene stanley abstract understanding the toxicity of amyloidogenic protein aggregates and designing therapeutic approaches require the knowledge of their structure. Molecular dynamics simulations reveal the inhibitory. Probing protein aggregation using discrete molecular dynamics. May 29, 2015 protein protein recognition and binding are governed by diffusion, noncovalent forces and conformational flexibility, entangled in a way that only molecular dynamics simulations can dissect at. It is also known that alzheimers disease is characterized by a substantial decrease of the amount of polyunsaturated lipids in the neuronal membranes of the frontal gray matter. Multiscale molecular dynamics of protein aggregation.
Molecular simulation offers a unique opportunity to gain. Biophysics copyright 2020 complete aggregation pathway. Publications chemical biology of protein aggregation. The generation of toxic nonnative protein conformers has emerged as a unifying thread among disorders such as alzheimers. Contrasting disease and nondisease protein aggregation by. Coupled molecular dynamics mediate long and shortrange. A molecular dynamics analysis of protein structural elements. Coarsegrained models for protein aggregation department of. A tool to construct automated markov state models from md simulations of molecular selfassembly and aggregation is presented here. Because the method used in this dmd approach does not require any knowledge of the native or any other state of the protein, it can be applied to study degenerative disorders associated with protein misfolding and aberrant protein aggregation. Molecular dynamics simulation suggests possible interaction. There are four ahelices, of which one is mainly buried in the protein interior, a threestranded psheet, and a long stretch of coiled loop.
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