Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report development a third-generation point-charge all-atom force field for proteins. Following earlier approach Cornell et al., charge set was obtained by fitting electrostatic potentials dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were energy profiles Ace-Ala-Nme Ace-Gly-Nme di-peptides...

A high density of galanin binding sites was found by using 125I-labeled galanin, iodinated chloramine-T, followed autoradiography in the ventral, but not dorsal, hippocampus rat. Lesions fimbria and septum caused disappearance a major population these sites, suggesting that large proportion them is localized on cholinergic nerve terminals septal afferents. As functional correlate to putative receptor it shown, both vivo vitro, concentration-dependent manner, inhibited evoked release...

High-accuracy ab initio folding has remained an elusive objective despite decades of effort. To explore the landscape villin headpiece subdomain HP35, we conducted two sets replica exchange molecular dynamics for 200 ns each and three conventional microsecond-long simulations, using AMBER FF03 force field a generalized-Born solvation model. The protein folded consistently to native state; lowest C α -rmsd from x-ray structure was 0.46 Å, - rmsd center most populated cluster 1.78 Å at 300 K....

Oligomerization of human islet amyloid polypeptide (IAPP) has been increasingly considered a pathogenic process in type II diabetes. Here structural features the IAPP monomer have probed using combination ion mobility mass spectrometry (IMS-MS) and all-atom replica exchange molecular dynamics (REMD) simulations. Three distinct conformational families are observed IMS experiments, two them identified as dehydrated solution structures on basis our simulation results: one is an extended...

Early oligomerization of human IAPP (hIAPP) is responsible for β-cell death in the pancreas and increasingly considered a primary pathological process linked to Type II Diabetes (T2D). Yet, assembly mechanism remains poorly understood, largely due inability conventional techniques probe distributions or detailed structures early oligomeric species. Here, we describe first experimental data on isolated unmodified dimers nonamyloidogenic rat (rIAPP). The experiments reveal that are more...

Abstract Based on the AMBER polarizable model (ff02), we have reoptimized parameters related to main‐chain (Φ, Ψ) torsion angles by fitting Boltzmann‐weighted average quantum mechanical (QM) energies of important regions (i.e., β, P II , α R and L regions). Following naming convention force field series, this release will be called ff02pol.rl The has been assessed both energetic comparison against QM data replica exchange molecular dynamics simulations short alanine peptides in water. For...

Congo red has been used to identify amyloid fibrils in tissues for more than 80 years and is also a weak inhibitor both amyloid-beta fibril formation toxicity. However, the specificity of binding its inhibition mechanism remain unclear. Using all-atom molecular dynamics simulations with explicit solvent model, we have identified characterized two specific modes molecules protofibril formed by an amyloidogenic fragment (GNNQQNY) yeast prion protein Sup35. The observation dual-mode was...

Translating sticky biological molecules-such as mussel foot proteins (MFPs)-into synthetic, cost-effective underwater adhesives with adjustable nano- and macroscale characteristics requires an intimate understanding of the glue's molecular interactions. To help facilitate next generation aqueous adhesives, we performed a combination surface forces apparatus (SFA) measurements replica-exchange dynamics (REMD) simulations on easy to prepare, Dopa-containing peptide (MFP-3s peptide), which...

Replica exchange molecular dynamics (REMD) method is one of the generalized-ensemble algorithms which performs random walk in energy space and helps a system to escape from local traps. In this work, we studied accuracy efficiency REMD by examining its ability reproduce results multiple extended conventional (MD) simulations enhance conformational sampling. Two sets with different initial configurations, fully other helical conformations, were conducted on fast-folding 21-amino-acid peptide...

IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that coexpressed and cosecreted along with insulin by pancreatic islet β-cells in response meals. IAPP plays physiological role glucose regulation; however, certain species, can aggregate this process linked β-cell death Type II Diabetes. Using replica exchange molecular dynamics extensive sampling (16 replicas per sequence 600 ns replica), we investigate structure of monomeric...

Amyloid cascades leading to peptide β-sheet fibrils and plaques are central many important diseases. Recently, intermediate assemblies of these were identified as the toxic agents that interact with cellular machinery. The relationship between transformation from natively unstructured assembly oligomers disease is in understanding onset development therapeutic agents. Research on this early oligomeric region has largely been unsuccessful since traditional techniques measure only ensemble...

Human islet amyloid polypeptide (hIAPP or Amylin) is a 37 residue hormone that cosecreted with insulin from the pancreatic islets. The aggregation of hIAPP plays role in progression type 2 diabetes and contributes to failure cell grafts. Despite considerable effort, little known about mode action IAPP inhibitors, this has limited rational drug design. Insulin one most potent inhibitors fibril formation, but its inhibition mechanism not understood. In study, mixtures insulin, as well separate...

Recently, certain C-terminal fragments (CTFs) of Aβ42 have been shown to be effective inhibitors toxicity. Here, we examine the interactions between shortest CTF in original series, Aβ(39-42), and full-length Aβ. Mass spectrometry results indicate that Aβ(39-42) binds directly Aβ monomers n = 2, 4, 6 oligomers. The Aβ42:Aβ(39-42) complex is further probed using molecular dynamics simulations. Although was expected bind hydrophobic C-terminus Aβ42, simulations show at several locations on...

Human telomeric DNA G-quadruplex has been identified as a good therapeutic target in cancer treatment. G-quadruplex-specific ligands that stabilize the have great potential to be developed anticancer agents. Two crystal structures (an apo form of parallel stranded human and its holo complex with BRACO19, potent ligand) solved, yet binding mechanism pathway remain elusive. In this study, we simulated free BRACO19 molecule using latest AMBER (OL15) ligand (GAFF2) force fields. Three modes...

Islet amyloid polypeptide (IAPP, amylin) forms pancreatic in type-2 diabetes, a process that contributes to the loss of β-cell mass disease. IAPP has been found all higher organisms examined, but not species form and ability do so correlates with primary sequence. The amyloidogenic potential fish IAPPs although have proposed as source for xenobiotic transplantation. sequence pufferfish (Takifugu rubripes) is known most divergent from human any reported sequence, differing at 11 positions...

Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage hindered by low selectivity towards DNA over duplex. High-resolution structures of in complex with neither single-stranded telomeric G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway was probed 27.5 µs molecular dynamics simulations free ligand (BRACO19) to and three different topological folds human (parallel, anti-parallel hybrid). The most stable modes were identified as end...

The mechanisms by which amyloidogenic peptides and proteins form soluble toxic oligomers remain elusive. We have studied the formation of partially ordered tetramers well-ordered octamers an hexapeptide NFGAIL (residues 22−27 human islet amyloid polypeptide) in our previous work. Continuing effort, we here probe β-sheet elongation process a combined total 2.0 μs molecular dynamics simulations with explicit solvent. In set 10 restrained to extended conformation, observed that main growth mode...