Molecular dynamics analysis of antibody recognition and escape by human H1N1 influenza hemagglutinin.

The antibody immunoglobulin (Ig) 2D1 is effective against the 1918 hemagglutinin (HA) and also known to cross-neutralize the 2009 pandemic H1N1 influenza HA through a similar epitope. However, the detailed mechanism of neutralization remains unclear. We conducted molecular dynamics (MD) simulations to study the interactions between Ig-2D1 and the HAs from the 1918 pandemic flu (A/South Carolina/1/1918, 18HA), the 2009 pandemic flu (A/California/04/2009, 09HA), a 2009 pandemic flu mutant (A/California/04/2009, 09HA_mut), and the 2006 seasonal flu (A/Solomon Islands/3/2006, 06HA).

Molecular-level simulation of pandemic influenza glycoproteins.

Computational simulation of pandemic diseases provides important insight into many disease features that may benefit public health. This is especially true for the influenza virus, a continuing global pandemic threat. Molecular or atomic-level investigation of influenza has predominantly focused on the two major virus glycoproteins, neuraminidase (NA) and hemagglutinin (HA).

Web servers and services for electrostatics calculations with APBS and PDB2PQR.

APBS and PDB2PQR are widely utilized free software packages for biomolecular electrostatics calculations. Using the Opal toolkit, we have developed a Web services framework for these software packages that enables the use of APBS and PDB2PQR by users who do not have local access to the necessary amount of computational capabilities. This not only increases accessibility of the software to a wider range of scientists, educators, and students but also increases the availability of electrostatics calculations on portable computing platforms.

Opal web services for biomedical applications.

Biomedical applications have become increasingly complex, and they often require large-scale high-performance computing resources with a large number of processors and memory. The complexity of application deployment and the advances in cluster, grid and cloud computing require new modes of support for biomedical research. Scientific Software as a Service (sSaaS) enables scalable and transparent access to biomedical applications through simple standards-based Web interfaces.

SMAP-WS: a parallel web service for structural proteome-wide ligand-binding site comparison.

The proteome-wide characterization and analysis of protein ligand-binding sites and their interactions with ligands can provide pivotal information in understanding the structure, function and evolution of proteins and for designing safe and efficient therapeutics. The SMAP web service (SMAP-WS) meets this need through parallel computations designed for 3D ligand-binding site comparison and similarity searching on a structural proteome scale. SMAP-WS implements a shape descriptor (the Geometric Potential) that characterizes both local and global topological properties of the protein structure and which can be used to predict the likely ligand-binding pocket [Xie,L.

Role of secondary sialic acid binding sites in influenza N1 neuraminidase.

Within influenza viral particles, the intricate balance between host cell binding and sialic acid receptor destruction is carefully maintained by the hemagglutinin (HA) and neuraminidase (NA) glycoproteins, respectively. A major outstanding question in influenza biology is the function of a secondary sialic acid binding site on the NA enzyme. Through a series of Brownian dynamics (BD) simulations of the avian N1, human pandemic N2, and currently circulating pandemic (H1)N1 enzymes, we have probed the role of this secondary sialic acid binding site in the avian N1 subtype.

Emerging methods for ensemble-based virtual screening.

Ensemble based virtual screening refers to the use of conformational ensembles from crystal structures, NMR studies or molecular dynamics simulations. It has gained greater acceptance as advances in the theoretical framework, computational algorithms, and software packages enable simulations at longer time scales. Here we focus on the use of computationally generated conformational ensembles and emerging methods that use these ensembles for discovery, such as the Relaxed Complex Scheme or Dynamic Pharmacophore Model.

Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective.

Hemagglutinins (HA's) from duck, swine, and human influenza viruses have previously been shown to prefer avian and human glycan receptor analogues with distinct topological profiles, pentasaccharides LSTa (alpha-2,3 linkage) and LSTc (alpha-2,6 linkage), in comparative molecular dynamics studies. On the basis of detailed analyses of the dynamic motions of the receptor binding domains (RBDs) and interaction energy profiles with individual glycan residues, we have identified approximately 30 residue positions in the RBD that present distinct profiles with the receptor analogues. Glycan binding constrained the conformational space sampling by the HA.

MEME SUITE: tools for motif discovery and searching.

The MEME Suite web server provides a unified portal for online discovery and analysis of sequence motifs representing features such as DNA binding sites and protein interaction domains. The popular MEME motif discovery algorithm is now complemented by the GLAM2 algorithm which allows discovery of motifs containing gaps. Three sequence scanning algorithms--MAST, FIMO and GLAM2SCAN--allow scanning numerous DNA and protein sequence databases for motifs discovered by MEME and GLAM2.

Distinct glycan topology for avian and human sialopentasaccharide receptor analogues upon binding different hemagglutinins: a molecular dynamics perspective.

Hemagglutinin (HA) binds to sialylated glycans exposed on the host cell surface in the initial stage of avian influenza virus infection. It has been previously hypothesized that glycan topology plays a critical role in the human adaptation of avian flu viruses, such as the potentially pandemic H5N1. Comparative molecular dynamics studies are complementary to experimental techniques, including glycan microarray, to understand the mechanism of species-specificity switch better.

Multiscale modeling in rodent ventricular myocytes.

There is a growing body of experimental evidence suggesting that the Ca(2+) signaling in ventricular myocytes is characterized by a high gradient near the cell membrane and a more uniform Ca(2+) distribution in the cell interior [1]--[7]. An important reason for this phenomenon might be that in these cells the t-tubular system forms a network of extracellular space, extending deep into the cell interior. This allows the electrical signal, that propagates rapidly along the cell membrane, to reach the vicinity of the sarcoplasmic reticulum (SR), where intracellular Ca(2+) required for myofilament activation is stored [1], [8]--[11].

Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase.

Avian influenza virus subtype H5N1 is a potential pandemic threat with human-adapted strains resistant to antiviral drugs. Although virtual screening (VS) against a crystal or relaxed receptor structure is an established method to identify potential inhibitors, the more dynamic changes within binding sites are neglected. To accommodate full receptor flexibility, we use AutoDock4 to screen the NCI diversity set against representative receptor ensembles extracted from explicitly solvated molecular dynamics simulations of the neuraminidase system.

MEME: discovering and analyzing DNA and protein sequence motifs.

MEME (Multiple EM for Motif Elicitation) is one of the most widely used tools for searching for novel 'signals' in sets of biological sequences. Applications include the discovery of new transcription factor binding sites and protein domains. MEME works by searching for repeated, ungapped sequence patterns that occur in the DNA or protein sequences provided by the user.

A comparative proteomics resource: proteins of Arabidopsis thaliana.

Using an integrative genome annotation pipeline (iGAP) for proteome-wide protein structure and functional domain assignment, we analyzed all the proteins of Arabidopsis thaliana. Three-dimensional structures at the level of the domain are assigned by fold recognition and threading based on a novel fold library that extends common domain classifications. iGAP is being applied to proteins from all available proteomes as part of a comparative proteomics resource.

Use of conserved key amino acid positions to morph protein folds.

By using three-dimensional (3D) structure alignments and a previously published method to determine Conserved Key Amino Acid Positions (CKAAPs) we propose a theoretical method to design mutations that can be used to morph the protein folds. The original Paracelsus challenge, met by several groups, called for the engineering of a stable but different structure by modifying less than 50% of the amino acid residues. We have used the sequences from the Protein Data Bank (PDB) identifiers 1ROP, and 2CRO, which were previously used in the Paracelsus challenge by those groups, and suggest mutation to CKAAPs to morph the protein fold.

CKAAPs DB: a Conserved Key Amino Acid Positions DataBase.

The Conserved Key Amino Acid Positions DataBase (CKAAPs DB) provides access to an analysis of structurally similar proteins with dissimilar sequences where key residues within a common fold are identified. CKAAPs may be important in protein folding and structural stability and function, and hence useful for protein engineering studies. This paper provides an update to the initial report of CKAAPs DB [Li et al.