The transmission of mutation effects in a multiprotein machine: A comprehensive metadynamics study of the cardiac thin filament.

The binding of Ca ions within the troponin core of the cardiac thin filament (CTF) regulates normal contraction and relaxation. Mutations within the troponin complexes are known to alter normal functions and result in the eventual development of cardiomyopathy. However, despite the importance of the problem, detailed microscopic knowledge of the mechanism of pathogenic effect of point mutations and their effects on the conformational free energy surface of CTF remains elusive.

Conformational Properties of Aβ Peptide Oligomers in Aqueous Ionic Liquid Solution: Insights from Molecular Simulation Studies.

Alzheimer's disease is a progressive irreversible neurological disorder with abnormal extracellular deposition of amyloid β (Aβ) peptides in the brain. We have carried out atomistic molecular dynamics simulations to investigate the size-dependent conformational properties of aggregated Aβ oligomers of different orders, namely, pentamer [O(5)], decamer [O(10)], and hexadecamer [O(16)] in aqueous solutions containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF]). The calculations revealed reduced peptide conformational fluctuations in O(5) and O(10) in the presence of the IL.

Counteraction Effects of Ammonium-Based Ionic Liquids on Urea-Induced Denaturation of α-Lactalbumin: A Comprehensive Molecular Simulation Study.

Ionic liquids (ILs) are known to stabilize protein conformations in aqueous medium. Importantly, ILs can also act as refolding additives in urea-driven denaturation of proteins. However, despite the importance of the problem, detailed microscopic understanding of the counteraction effects of ILs on urea-induced protein denaturation remains elusive.

Exploring the Heterogeneous Dynamical Environment at the Interface of Aβ Peptide in Aqueous Ionic Liquid Solution.

In this study, we have investigated the heterogeneous dynamical environment around an ensemble of full-length amyloid-β (Aβ) peptide monomers in binary aqueous solution containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF] as a co-solvent. Atomistic molecular dynamics (MD) simulations have been employed with the aim of understanding the effect of the IL on the distribution of water molecules and IL components around distinct segments of the peptide. As compared to pure aqueous medium, locally heterogeneous restricted water motions at the interface have been spotted in the presence of the IL.

Microscopic Understanding of the Conformational Stability of the Aggregated Nonamyloid β Components of α-Synuclein.

Self-association of α-synuclein peptides into oligomeric species and ordered amyloid fibrils is associated with Parkinson's disease, a progressive neurodegenerative disorder. In particular, the peptide domain formed between the residues Glu-61 (or E61) and Val-95 (or V95) of α-synuclein, typically termed the "nonamyloid β component" (NAC), is known to play critical roles in forming aggregated structures. In this work, we have employed molecular dynamics simulations to explore the conformational properties and relative stabilities of aggregated protofilaments of different orders, namely, tetramer (P(4)), hexamer (P(6)), octamer (P(8)), decamer (P(10)), dodecamer (P(12)), and tetradecamer (P(14)), formed by the NAC domains of α-synuclein.

Impact of an Ionic Liquid on Amino Acid Side Chains: A Perspective from Molecular Simulation Studies.

Ionic liquids (ILs) are known to modify the structural stability of proteins. The modification of the protein conformation is associated with the accumulation of ILs around the amino acid (AA) side chains and the nature of interactions between them. To understand the microscopic picture of the structural arrangements of ILs around the AA side chains, room temperature molecular dynamics (MD) simulations have been carried out in this work with a series of hydrophobic, polar and charged AAs in aqueous solutions containing the IL 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF]) at 2 M concentration.

Exploring the Dynamic Heterogeneity at the Interface of a Protein in Aqueous Ionic Liquid Solutions.

Room temperature molecular dynamics (MD) simulations of the globular protein α-lactalbumin in aqueous solutions containing BMIM (1-butyl-3-methylimidazolium) based ionic liquids (ILs) with a series of Hofmeister anions have been carried out. In particular, effects of anions of different shapes/sizes and hydrophobic/hydrophilic characters, namely, thiocyanate (SCN), dicyanamide (DCA), methyl sulfate (MS), triflate (TFO), and bis(trifluoromethane) sulfonimide (TFN) on the heterogeneous dynamic environment at the interface around the protein have been explored. The calculations revealed exchange of population between water and IL cation-anion components beyond the first layer of bound water molecules at the protein surface.

Dynamic Heterogeneity at the Interface of an Intrinsically Disordered Peptide.

It is believed that water around an intrinsically disordered protein or peptide (IDP) in an aqueous environment plays an important role in guiding its conformational properties and aggregation behavior. However, despite its importance, only a handful of studies exploring the correlation between the conformational motions of an IDP and the microscopic properties of water at its surface are reported. Attempts have been made in this work to study the dynamic properties of water present in the vicinity of α-synuclein, an IDP associated with Parkinson's disease (PD).

Contrasting Effects of Ionic Liquids of Varying Degree of Hydrophilicity on the Conformational and Interfacial Properties of a Globular Protein.

Ionic liquids (ILs), depending on their cation-anion combinations, are known to influence the conformational properties and activities of proteins in a nonuniform manner. To obtain microscopic understanding of such influence, it is important to characterize protein-IL interactions and explore the modified solvation environment around the protein. In this work, molecular dynamics (MD) simulations of the globular protein α-lactalbumin have been carried out in aqueous IL solutions containing 1-butyl-3-methylimidazolium cations (BMIM) in combination with a series of anions with varying degree of hydrophilicity, namely, hexafluorophosphate (PF), ethyl sulfate (ETS), acetate (OAc), chloride (Cl), dicyanamide (DCA), and nitrate (NO) .

Microscopic Understanding of the Effect of Ionic Liquid on Protein from Molecular Simulation Studies.

We have performed molecular dynamics (MD) simulations of the protein α-lactalbumin in aqueous solution containing the ionic liquid (IL) 1-butyl-3-methyl imidazolium tetrafluoroborate ([BMIM][BF]) as the cosolvent at different concentrations. Attempts have been made to obtain quantitative understanding of the effects of the IL on the conformational features of the protein as well as the distributions of the IL and water around it. The calculations revealed enhanced rigidity of the protein with reduced conformational fluctuations and increasingly correlated local motions in the presence of the IL.