De Novo Hydration of Cryo-EM Reconstructions through Molecular Dynamics Simulations of the Excess Chemical Potential.

Predicting the precise positions of water molecules at the protein interface remains a formidable challenge, fueling active research in this field. Here, we present a novel approach based on molecular dynamics simulations that utilizes statistical thermodynamic signatures of water at protein interfaces to improve the accuracy of water placement in cryo-EM maps, with apoferritin as a model benchmark system. The interaction energy of solvent with the protein is insufficient to distinguish between high- and lower-consensus water positions, consistent with reports of earlier work.

Insights into amyloid-β misfolding: The impact of histidine tautomerism and Au(111) surfaces through MD simulations and 2DIR spectroscopy.

The structural and dynamic properties of histidine tautomeric isomers (δδδ and εεε) in the amyloid-β (Aβ40) peptide are thoroughly examined, both in their isolated state and in interaction with the Au(111) surface, to explore their behavior in diverse environments. Utilizing molecular dynamics simulations and advanced 2D spectroscopy techniques, we reveal that the Au(111) surface significantly modulates the peptides' conformational flexibility, hydrogen bonding patterns, and secondary structures. Notably, the presence of gold leads to enhanced stability and a reduction in β-sheet formation, especially for the δδδ isomer, favoring the formation of coils and α-helices instead.

Acceleration with Interpretability: A Surrogate Model-Based Collective Variable for Enhanced Sampling.

Most enhanced sampling methods facilitate the exploration of molecular free energy landscapes by applying a bias potential along a reduced dimensional collective variable (CV) space. The success of these methods depends on the ability of the CVs to follow the relevant slow modes of the system. Intuitive CVs, such as distances or contacts, often prove inadequate, particularly in biological systems involving many coupled degrees of freedom.

Histidine tautomerism-mediated transthyretin amyloidogenesis: A molecular insight.

Characterization of the conformational alterations involved in monomer misfolding is essential for elucidating the molecular basis of the initial stage of protein accumulation. Here, we report the first structural analyses of transthyretin (TTR) (26-57) fragments with two histidine tautomeric states (δ; NH and ε; NH) using replica-exchange molecular dynamics (REMD) simulations. Explaining the organizational properties and misfolding procedure is challenging because the δ and ε configurations can occur in the free neutral state.

Exposure to the electric field: A potential way to block the aggregation of histidine tautomeric isomers of β-amyloid.

Controlling protein misfolding and accumulation in neurodegeneration is a challenge in chemical neuroscience. The application of appropriate electric fields (EFs) can be a potential noninvasive therapy to treat neuro disorders. The effect of EFs of varying intensities and directions on the conformational dynamics of β-Amyloid40 (Aβ40) under histidine tautomerism has been investigated for the first time.

Monitoring early-stage β-amyloid dimer aggregation by histidine site-specific two-dimensional infrared spectroscopy in a simulation study.

Monitoring early-stage β-amyloid (Aβ) dimerization is a formidable challenge for understanding neurological diseases. We compared β-sheet formation and histidine site-specific two-dimensional infrared (2D IR) spectroscopic signatures of Aβ dimers with different histidine states (δ; N-H, ε; N-H, or π; both protonated). Molecular dynamics (MD) simulations revealed that β-sheet formation is favored for the δδδ:δδδ and πππ:πππ tautomeric isomers showing strong couplings and frequent contacts between the central hydrophobic core and C-terminus compared with the εεε:εεε isomer.

Mechanistic Insights into the Polymorphic Associations and Cross-Seeding of Aβ and hIAPP in the Presence of Histidine Tautomerism: An All-Atom Molecular Dynamic Study.

Hundreds of millions of people around the world have been affected by Type 2 diabetes (T2D) which is a metabolic disorder. Clinical research has revealed T2D as a possible risk factor for Alzheimer's disease (AD) development (and vice versa). Amyloid-β (Aβ) and human islet amyloid polypeptide are the main pathological species in AD and T2D, respectively.

Unraveling the Histidine Tautomerism Effect on the Initial Stages of Prion Misfolding: New Insights from a Computational Perspective.

The aggregation and structural conversion of normal prion peptide (PrP) into the pathogenic scrapie form (PrP), which can act as a seed to enhance prion amyloid fiber formation, is believed to be a crucial event in prionopathies. Previous research suggests that the prion monomer may play an important role in oligomer generation during disease pathogenesis. In the present study, extensive replica-exchange molecular dynamics (REMD) simulations were conducted to explore the conformational characteristics of the huPrP (125-160) monomer under the histidine tautomerism effect.

Histidine Tautomerism Driving Human Islet Amyloid Polypeptide Aggregation in the Early Stages of Diabetes Mellitus Progression: Insight at the Atomistic Level.

Early oligomerization of human islet amyloid polypeptide (hIAPP), which is accountable for β-cell death, has been implicated in the progression of type 2 diabetes mellitus. Some researches have shown the connection between hIAPP and Alzheimer's disease as well. However, the mechanism of peptide accumulation and associated cytotoxicity remains unclear.

Molecular mechanism of amyloidogenicity and neurotoxicity of a pro-aggregated tau mutant in the presence of histidine tautomerism replica-exchange simulation.

The accumulation of ΔK280 tau mutant resulting in neurotoxic oligomeric aggregates is an important but yet mysterious procedure in Alzheimer's disease (AD) development. Recently, we proposed a histidine tautomerization hypothesis of tau fibrillogenesis for the pathobiology of AD and other neuro diseases. However, the influence of neutral histidine tautomeric states on tau mutation is still unclear.

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau Monomer.

Histidine tautomerism is considered a crucial component that affects the constitutional and accumulation characteristics of the tau monomer in the neutral condition, which are connected with the pathobiology of Alzheimer's disease (AD). Interpreting the organizational characteristics and accumulation procedure is a challenging task because two tautomeric conformations (the N-H or N-H tautomer) can occur in the open neutral condition. In the current work, replica-exchange molecular dynamics (REMD) simulations were performed to investigate the structural properties of the tau monomer considering the histidine tautomeric effect.

Insights into amyotrophic lateral sclerosis linked Pro525Arg mutation in the fused in sarcoma protein through analysis and molecular dynamics simulation.

A novel heterozygous mutation, Pro525Arg (P525R) in the Fused in Sarcoma (FUS) protein is predominant in young adult females with familial amyotrophic lateral sclerosis (fALS). Investigation of the biophysical characteristics of this mutation through analysis of protein conformation could provide insights into the pathogenic mechanism of amyotrophic lateral sclerosis (ALS). Here, several computational prediction tools were applied to investigate the effect of P525R on the stability, flexibility, and function of FUS.