Self-assembling peptide biomaterials: Insights from spontaneous and enhanced sampling molecular dynamics simulations

Chemical Physics Reviews, Journal Year: 2023, Volume and Issue: 4(2)

Published: April 21, 2023

Peptide self-assembly is the process by which peptide molecules aggregate into low dimensional (1D, 2D) or 3D ordered materials with potential applications ranging from drug delivery to electronics. Short peptides are particularly good candidates for forming supramolecular assemblies due relatively simple structure and ease of modulating their achieve required material properties. The experimental resolution fibrous peptide-based nanomaterials as atomic coordinates remains challenging. For surface-mediated assembly in particular, it typically not feasible resolve multiple conformationally distinct surface bound structures experiment. mechanisms also remain elusive interchange complex interactions time length scales involved process. solution, mediated surfaces, driven specific between water, competing within and/or units and, latter case, an interplay solvent adsorption onto a proximal surface. Computational methodologies have proven beneficial elucidating formed during molecular driving it, hence scope facilitating development functional medical biotechnological applications. In this perspective, computational methods that provided insights formation biomaterials, all-atom-resolved presented. Established recently emerged simulation approaches reviewed focus on relevant assembly, including all-atom coarse-grained “brute force” dynamics well enhanced sampling methodologies: umbrella sampling, steered replica exchange dynamics, variants metadynamics. These been shown contribute details yet available experimentally, advance our understanding processes biomaterial formation. review includes summary current state methods, terms strengths limitations application self-assembling biomaterials.

Language: Английский

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Conformational Plasticity in α-Synuclein and How Crowded Environment Modulates It

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(18), P. 4032 - 4049

Published: April 28, 2023

A 140-residue intrinsically disordered protein (IDP), α-synuclein (αS), is known to adopt conformations that are vastly plastic and susceptible environmental cues crowders. However, the inherently heterogeneous nature of αS has precluded a clear demarcation its monomeric precursor between aggregation-prone functionally relevant aggregation-resistant states how crowded environment could modulate their mutual dynamic equilibrium. Here, we identify an optimal set distinct metastable in aqueous media by dissecting 73 μs-long molecular dynamics ensemble via building comprehensive Markov state model (MSM). Notably, most populated corroborates with dimension obtained from PRE-NMR studies monomer, it undergoes kinetic transition at diverse time scales weakly random-coil-like globular protein-like state. subjecting results nonmonotonic compaction these conformations, thereby skewing either introducing new tertiary contacts or reinforcing innate contacts. The early stage dimerization process found be considerably expedited presence crowders, albeit promoting nonspecific interactions. Together this, using extensively sampled αS, this exposition demonstrates environments can potentially conformational preferences IDP promote inhibit aggregation events.

Language: Английский

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Towards rational computational peptide design

Frontiers in Bioinformatics, Journal Year: 2022, Volume and Issue: 2

Published: Oct. 21, 2022

Peptides are prevalent in biology, mediating as many 40% of protein-protein interactions, and involved other cellular functions such transport signaling. Their ability to bind with high specificity make them promising therapeutical agents intermediate properties between small molecules large biologics. Beyond their biological role, peptides can be programmed self-assembly, they already being used for diverse oligonuclotide delivery, tissue regeneration or drugs. However, the transient nature interactions has limited number structures knowledge binding affinities available–and flexible success computational pipelines that predict these molecules. Fortunately, recent advances experimental creating new opportunities this field. We starting see predictions complex structures, thermodynamic kinetic properties. believe following years will lead robust rational peptide design similar those applied molecule drug discovery.

Language: Английский

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Rational drug design targeting intrinsically disordered proteins

Wiley Interdisciplinary Reviews Computational Molecular Science, Journal Year: 2023, Volume and Issue: 13(6)

Published: Aug. 26, 2023

Abstract Intrinsically disordered proteins (IDPs) are that perform important biological functions without well‐defined structures under physiological conditions. IDPs can form fuzzy complexes with other molecules, participate in the formation of membraneless organelles, and function as hubs protein–protein interaction networks. The malfunction causes major human diseases. However, drug design targeting remains challenging due to their highly dynamic interactions. Turning into druggable targets provides a great opportunity extend target‐space for novel discovery. Integrative structural biology approaches combine information derived from computational simulations, artificial intelligence/data‐driven analysis experimental studies have been used uncover interactions IDPs. An increasing number ligands directly bind found either by target‐based screening or phenotypic screening. Along understanding IDP binding its partners, structure‐based strategies, especially conformational ensemble‐based ligand computer‐aided optimization algorithms, greatly accelerated development ligands. It is inspiring several IDP‐targeting small‐molecule peptide drugs advanced clinical trials. new methods need be further developed efficiently discovering optimizing specific potent vast interactions, expected become valuable treasure targets. This article categorized under: Structure Mechanism > Computational Biochemistry Biophysics

Language: Английский

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Effect of Terahertz Waves on the Structure of the Aβ42 Monomer, Dimer, and Protofibril: Insights from Molecular Dynamics Simulations

ACS Chemical Neuroscience, Journal Year: 2023, Volume and Issue: 14(23), P. 4128 - 4138

Published: Nov. 20, 2023

Amyloid-β (Aβ) and its assemblies play important roles in the pathogenesis of Alzheimer's disease (AD). Recent studies conducted by experimental computational researchers have extensively explored structure, assembly, influence biomolecules cell membranes on Aβ. However, impact terahertz waves structures Aβ monomers aggregates remains largely unexplored. In this study, we systematically investigate molecular mechanisms which affect structure Aβ42 monomer, dimer, tetramer through all-atom dynamics (MD) simulations. Our findings indicate that at a specific frequency (42.55 THz) can enhance intramolecular intermolecular interactions monomer respectively, resonating with symmetric stretching mode –COO– groups bending/stretching –CH3 groups. Consequently, β-structure content is greatly increased, binding energy between dimer significantly enhanced. Additionally, our observations suggest mildly stabilize tetrameric protofibrils enhancing among peripheral peptides. Furthermore, also investigated effect Aβ42. The present study contributes to better understanding external fields biobehavior peptides may shed some light potential risks associated electromagnetic field radiation.

Language: Английский

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CoVAMPnet: Comparative Markov State Analysis for Studying Effects of Drug Candidates on Disordered Biomolecules

JACS Au, Journal Year: 2024, Volume and Issue: 4(6), P. 2228 - 2245

Published: May 28, 2024

Computational study of the effect drug candidates on intrinsically disordered biomolecules is challenging due to their vast and complex conformational space. Here, we developed a comparative Markov state analysis (CoVAMPnet) framework quantify changes in distribution dynamics biomolecule presence absence small organic candidate molecules. First, molecular trajectories are generated using enhanced sampling, molecule candidates, ensembles soft models (MSMs) learned for each system unsupervised machine learning. Second, these MSMs aligned across different systems based solution an optimal transport problem. Third, directional importance inter-residue distances assignment states assessed by discriminative aggregated neural network gradients. This final step provides interpretability biophysical context MSMs. We applied this novel computational assess effects ongoing phase 3 therapeutics tramiprosate (TMP) its metabolite 3-sulfopropanoic acid (SPA) Aβ42 peptide involved Alzheimer's disease. Based adaptive sampling CoVAMPnet analysis, observed that both TMP SPA preserved more structured conformations interacting nonspecifically with charged residues. impacted than TMP, protecting α-helices suppressing formation aggregation-prone β-strands. Experimental analyses showed only mild TMP/SPA activity enhancement endogenous metabolization into SPA. Our data suggest may also target other Aβ peptides. The method broadly applicable behavior biomolecules.

Language: Английский

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Modeling the Structure and Interactions of Intrinsically Disordered Peptides with Multiple Replica, Metadynamics-Based Sampling Methods and Force-Field Combinations

Journal of Chemical Theory and Computation, Journal Year: 2022, Volume and Issue: 18(3), P. 1915 - 1928

Published: Feb. 17, 2022

Intrinsically disordered proteins play a key role in many biological processes, including the formation of biomolecular condensates within cells. A detailed characterization their configurational ensemble and structure-function paradigm is crucial for understanding activity exploiting them as building blocks material sciences. In this work, we incorporate bias-exchange metadynamics parallel-tempering well-tempered with CHARMM36m CHARMM22* to explore structural thermodynamic characteristics short archetypal sequence derived from DEAD-box protein. The conformational landscapes emerging our simulations are largely congruent across methods force fields. Nevertheless, differences fine details emerge varying combinations force-fields sampling methods. For protein, analysis identifies features that help explain low propensity undergo self-association vitro, which common all force-field/sampling method combinations. Overall, work demonstrates importance using multiple force-field accurate information study proteins.

Language: Английский

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Comparative molecular dynamics simulations of pathogenic and non-pathogenic huntingtin protein monomers and dimers

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: April 10, 2023

Polyglutamine expansion at the N-terminus of huntingtin protein exon 1 (Htt-ex1) is closely associated with a number neurodegenerative diseases, which result from aggregation increased polyQ repeat. However, underlying structures and mechanism are still poorly understood. We performed microsecond-long all-atom molecular dynamics simulations to study folding dimerization Htt-ex1 (about 100 residues) non-pathogenic pathogenic lengths, uncovered substantial differences. The monomer adopts long α-helix that includes most residues, forms interaction interface for dimerization, PPII-turn-PPII motif in proline-rich region. In monomer, region disordered, leading compact many intra-protein interactions formation short β-sheets. Dimerization can proceed via different modes, where those involving N-terminal headpiece bury more hydrophobic residues thus stable. Moreover, dimers interacts region, slows

Language: Английский

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Delving into the crucial role of the initial structure in the dynamic and self-assembly of amyloid beta

Biochemical and Biophysical Research Communications, Journal Year: 2025, Volume and Issue: 758, P. 151652 - 151652

Published: March 17, 2025

Language: Английский

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Tangeretin protects against Aβ1-42-induced toxicity and exploring mitochondria-lysosome interactions in HT22 cells

Biochemical and Biophysical Research Communications, Journal Year: 2025, Volume and Issue: unknown, P. 151769 - 151769

Published: April 1, 2025

Language: Английский

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