A5032769652- Protein Structure and Dynamics
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Lipid Membrane Structure and Behavior
- Computational Drug Discovery Methods
- Alzheimer's disease research and treatments
- Mass Spectrometry Techniques and Applications
- Spectroscopy and Quantum Chemical Studies
- DNA and Nucleic Acid Chemistry
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Hemoglobin structure and function
- Molecular spectroscopy and chirality
- Machine Learning in Bioinformatics
- Biochemical and Structural Characterization
- Ubiquitin and proteasome pathways
- Advanced Chemical Physics Studies
- Cardiovascular Effects of Exercise
- Proteins in Food Systems
- Drug Transport and Resistance Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Cardiomyopathy and Myosin Studies
- Machine Learning in Materials Science
- Biochemical Acid Research Studies
- thermodynamics and calorimetric analyses
- Protein Degradation and Inhibitors
Clark University
2011-2024
Florida State University
1996-2007
National High Magnetic Field Laboratory
1996-2007
Beijing University of Chemical Technology
2006
University of California, San Francisco
2000-2003
PharmChem (United States)
2003
Boston University
1997-2002
University of Utah
2000
Scripps Research Institute
2000
A historical perspective on the application of molecular dynamics (MD) to biological macromolecules is presented. Recent developments combining state-of-the-art force fields with continuum solvation calculations have allowed us reach fourth era MD applications in which one can often derive both accurate structure and relative free energies from trajectories. We illustrate such nucleic acid duplexes, RNA hairpins, protein folding trajectories, protein−ligand, protein−protein, protein−nucleic...
Abstract The MM‐PBSA (Molecular Mechanics–Poisson–Boltzmann surface area) method was applied to the human Growth Hormone (hGH) complexed with its receptor assess both validity and limitations of computational alanine scanning approach. A 400‐ps dynamical trajectory fully solvated complex simulated at 300 K in a 101 Å×81 Å×107 Å water box using periodic boundary conditions. Long‐range electrostatic interactions were treated particle mesh Ewald (PME) summation method. Equally spaced snapshots...
In this study, we compare the calculated and experimental binding free energies for a combinatorial library of inhibitors cathepsin D (CatD), an aspartyl protease. Using molecular dynamics (MD)-based, continuum solvent method (MM-PBSA), are able to reproduce affinity set seven with average error ca. 1 kcal/mol correlation coefficient 0.98. By comparing dynamical conformations complexed CatD initial generated by CombiBuild (University California, San Francisco, CA, 1995), have found that...
An algorithm for the calculation of reaction paths between known reactant and product states in systems low or high dimension is described. The optimal path defined as maximum flux a diffusive dynamics assuming isotropic friction. resulting temperature dependent independent magnitude Comparison made with number algorithms designed minimum-energy paths. Applications to two model potentials an extended atom dipeptide are presented. applications demonstrate ability isolate temperature-dependent...
Small oligomers formed early in the process of amyloid fibril formation may be major toxic species Alzheimer's disease. We investigate stages aggregation for tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations 12, 24, 36 chains. A variety small metastable aggregates form dissolve until aggregate a critical size conformation arises. However, stable oligomers, which are beta-sheet-rich feature many hydrophobic contacts, not always...
We have developed a fast procedure to predict solvation free energies for both organic and biological molecules. This model is based on weighted solvent accessible surface area (WSAS). Least-squares fittings been applied optimize the weights of SAS different atom types in order reproduce experimental energies. Good agreement with results has obtained. For 184-molecule set (model I), which there are 1-octanol, we achieved an average error 0.36 kcal/mol, better than that SM5.42R universal...
Dimensionality reduction methods have been widely used to study the free energy landscapes and low-free pathways of molecular systems. It was shown that non-linear dimensionality-reduction gave better embedding results than linear methods, such as principal component analysis, in some simple In this study, we evaluated several non locally embedding, Isomap, diffusion maps, well analysis from equilibrium folding/unfolding trajectory second β-hairpin B1 domain streptococcal protein G. The...
The amyloid fibrils formed by islet polypeptide (IAPP) are associated with type II diabetes. One of the proposed mechanisms toxicity IAPP is that it causes membrane damage. fatal mutation S20G human was reported to lead early onset diabetes and high tendency formation in vitro. Characterizing structural features mutant its monomeric state experimentally difficult because unusually fast aggregation rate. Computational work complements experimental studies. We performed a series molecular...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLipid-Peptide Interface: Valine Conformation and Dynamics in the Gramicidin ChannelK.-C. Lee, S. Huo, T. A. CrossCite this: Biochemistry 1995, 34, 3, 857–867Publication Date (Print):January 1, 1995Publication History Published online1 May 2002Published inissue 1 January 1995https://pubs.acs.org/doi/10.1021/bi00003a020https://doi.org/10.1021/bi00003a020research-articleACS PublicationsRequest reuse permissionsArticle Views91Altmetric-Citations39LEARN...
Classical molecular dynamics simulation is employed to study the photodissociated B-states of carbon monoxymyoglobin. Four independent 10 ps dynamical trajectories fully solvated protein, in a box 2988 water molecules using periodic boundary conditions, were simulated at 300 K starting from equilibrium deoxymyoglobin structure. Two prototypical protein conformational substates, defined by conformation distal histidine, sampled 1.5 ns trajectory solvated, room temperature deoxymyoglobin. The...
The MaxFlux reaction path algorithm was used to isolate optimal transition pathways for the coil-to-helix in polyalanine. Eighteen pathways, each connecting one random coil configuration with an ideal alpha-helical configuration, were computed and analyzed. pathway energetics mechanism analyzed terms of progression peptide nonbonded contact formation, helicity, end-to-end distance energetics. It found that (1) localized turns characterized by i, i + 3 hydrogen bonds form early stages...
Functional regulation of proteins is central to living organisms. Here it shown that a nonfunctional conformational state polypeptide can be kinetically trapped in lipid bilayer environment. This metastable structure stable for weeks just above the phase transition temperature lipid. When samples are incubated several days at 68 degrees C, 50% conformation converts minimum-energy functional state. result suggests possibility another mechanism protein activity may available membrane proteins:...
Transthyretin (TTR) is one of the known human amyloidogenic proteins. Its native state a homotetramer with each monomer having beta-sandwich structure. Strong experimental evidence suggests that TTR dissociates into monomeric intermediates and monomers subsequently self-assemble to form amyloid deposits insoluble fibrils. However, details on early steps along pathway formation are unclear, although various approaches resolutions at molecular or residue level have provided some clues. It...
Human transthyretin (TTR) is an amyloidogenic protein whose aggregation associated with several types of amyloid diseases. The following mechanism TTR formation has been proposed. tetramer at first dissociates into native monomers, which the rate-limiting step in fibril formation. monomeric species then partially unfold to form intermediates that subsequently undergo a downhill self-assembly process. deposit can be facilitated by disease-associated point mutations. However, only subtle...
Interstrand conformational rearrangements of human transthyretin peptide (TTR(105−115)) within dimeric aggregates were simulated by means molecular dynamics (MD) with implicit solvation model for a total length 48 μs. The conformations sampled in the MD simulations clustered to identify free energy minima without any projections surface. A connected graph was constructed nodes (=clusters) and edges corresponding transitions between nodes, respectively. This which reflects complexity surface...
A 4-μs molecular dynamics simulation of the second β-hairpin B1 domain streptococcal protein G is used to characterize free energy surface and evaluate different configurational entropy estimators. From equilibrium folding−unfolding trajectory, 200 000 conformers are clustered according their root-mean-square deviation (RMSD). The height barrier between pairs clusters found be significantly correlated with pairwise RMSD. Relative energies relative entropies determined by explicit evaluation...
In this paper we present a method to calculate temperature-dependent optimized conformational transition pathways. This is based on the maximization of flux derived from Smoluchowski equation and implemented with probabilistic roadmap algorithm. We have tested algorithm four systems [Formula: see text] Müller potential, three-hole alanine dipeptide, folding β-hairpin. Comparison made existing algorithms designed for calculation protein The applications demonstrate ability isolate optimal...
Abstract Pauling and Corey proposed a pleated‐sheet configuration, now called α‐sheet, as one of the protein secondary structures in addition to α‐helix β‐sheet. Recently, it has been suggested that α‐sheet is common feature amyloidogenic intermediates. We have investigated stability antiparallel β‐sheet two conformations solution phase using density functional theoretical method. The peptides are modeled two‐strand acetyl‐(Ala) 2 ‐ N ‐methylamine. Using stages geometry optimization single...
The thermodynamics and kinetics of protein folding conformational changes are governed by the underlying free energy landscape. However, multidimensional nature landscape makes it difficult to describe. We propose use a weighted-graph approach depict with nodes on graph representing states edge weights reflecting barriers between states. Our is constructed from molecular dynamics trajectory does not involve projecting multi-dimensional onto low-dimensional space defined few order parameters....