Specific Residue Interactions Regulate the Binding of Dengue Antigens to Broadly Neutralizing EDE Antibodies.

Antibodies binding to antigens present on the dengue virus (DENV) represent the main defense mechanism of the host organism against the pathogen. Among the antibodies elicited by DENV and that bind to DII of protein E, EDE1-C8 can bind all DENV serotypes. Our analysis reveals the key residues in this interaction as well as structurally conserved hydrogen bonds located at the binding interface.

Conformational dynamics and free energy of BHRF1 binding to Bim BH3.

The interaction between the Bim BH3 peptide and the viral protein BHRF1 is pivotal to understanding the fundamental molecular details of the mechanism used by the Epstein-Barr virus to trick the mammalian immune system. Here, we study the mechanism of binding/unbinding and compute the free energy for the association of the Bim peptide to the BHRF1 protein. Key elements of the binding mechanism are the conformational rearrangement together with a main free energy barrier of 11.

Free Energy of Binding and Mechanism of Interaction for the MEEVD-TPR2A Peptide-Protein Complex.

The association between the MEEVD C-terminal peptide from the heat shock protein 90 (Hsp90) and tetratricopeptide repeat A (TPR2A) domain of the heat shock organizing protein (Hop) is a useful prototype to study the fundamental molecular details about the Hop-Hsp90 interaction. We study here the mechanism of binding/unbinding and compute the standard binding free energy and potential of mean force for the association of the MEEVD peptide to the TPR2A domain using the Adaptive Biasing Force (ABF) methodology. We observe conformational changes of the peptide and the protein receptor induced by binding.

Molecular simulations of micellar aggregation of polysorbate 20 ester fractions and their interaction with N-phenyl-1-naphthylamine dye.

Micellar aggregation behavior of polysorbate 20 (PS20) has generated significant interest because of the wide use of PS20 as a surfactant to minimize protein surface adsorption and mitigate protein aggregation. Thus, there is a need for better molecular understanding of what drives the biophysical behavior of PS20 in solution. We observe that a complex amphipathic PS20 molecule, which contains both hydrophobic tail and relatively large hydrophilic head, self-associates strongly within the course of a molecular dynamics simulation performed with a fully atomistic representation of the molecule and an explicit water solvent model.

Modeling of protein-anion exchange resin interaction for the human growth hormone charge variants.

Modeling ion exchange chromatography (IEC) behavior has generated significant interest because of the wide use of IEC as an analytical technique as well as a preparative protein purification process; indeed there is a need for better understanding of what drives the unique behavior of protein charge variants. We hypothesize that a complex protein molecule, which contains both hydrophobic and charged moieties, would interact strongly with an in silico designed resin through charged electrostatic patches on the surface of the protein. In the present work, variants of recombinant human growth hormone that mimic naturally-occurring deamidation products were produced and characterized in silico.

Full kinetics of CO entry, internal diffusion, and exit in myoglobin from transition-path theory simulations.

We use Markovian milestoning molecular dynamics (MD) simulations on a tessellation of the collective variable space for CO localization in myoglobin to estimate the kinetics of entry, exit, and internal site-hopping. The tessellation is determined by analysis of the free-energy surface in that space using transition-path theory (TPT), which provides criteria for defining optimal milestones, allowing short, independent, cell-constrained MD simulations to provide properly weighted kinetic data. We coarse grain the resulting kinetic model at two levels: first, using crystallographically relevant internal cavities and their predicted interconnections and solvent portals; and second, as a three-state side-path scheme inspired by similar models developed from geminate recombination experiments.

Molecular simulations of the pairwise interaction of monoclonal antibodies.

Molecular simulations are employed to compute the free energy of pairwise monoclonal antibodies (mAbs) association using a conformational sampling algorithm with a scoring function. The work reported here is aimed at investigating the mAb-mAb association driven by weak interactions with a computational method capable of predicting experimental observations of low binding affinity. The simulations are able to explore the free energy landscape.

Correction: Chimeric Rhinoviruses Displaying MPER Epitopes Elicit Anti-HIV Neutralizing Responses.

[This corrects the article on p. e72205 in vol. 8.

Chimeric rhinoviruses displaying MPER epitopes elicit anti-HIV neutralizing responses.

Background: The development of an effective AIDS vaccine has been a formidable task, but remains a critical necessity. The well conserved membrane-proximal external region (MPER) of the HIV-1 gp41 glycoprotein is one of the crucial targets for AIDS vaccine development, as it has the necessary attribute of being able to elicit antibodies capable of neutralizing diverse isolates of HIV.

Methodology/principle Findings: Guided by X-ray crystallography, molecular modeling, combinatorial chemistry, and powerful selection techniques, we designed and produced six combinatorial libraries of chimeric human rhinoviruses (HRV) displaying the MPER epitopes corresponding to mAbs 2F5, 4E10, and/or Z13e1, connected to an immunogenic surface loop of HRV via linkers of varying lengths and sequences.

Transition-Path Theory Calculations on Non-Uniform Meshes in Two and Three Dimensions using Finite Elements.

Rare events between states in complex systems are fundamental in many scientific fields and can be studied by building reaction pathways. A theoretical framework to analyze reaction pathways is provided by transition-path theory (TPT). The central object in TPT is the committor function, which is found by solution of the backward-Kolmogorov equation on a given potential.

A computational study of water and CO migration sites and channels inside myoglobin.

Pathways are computed for transport of HO and CO in myoglobin (Mb), using the single sweep and zero-temperature string methods in a fully atomistic, explicitly solvated model system. Our predictions of sites and barriers in the pathways for CO transport agree with previous studies. For HO, we predict a binding site in the distal pocket (DP), in agreement with crystallographic observations, and another one close to Leu 29 which explains the importance of this residue in controlling the pocket's hydrophobicity, as well as disordered minima in the largely apolar xenon cavities.

Theory of binless multi-state free energy estimation with applications to protein-ligand binding.

The weighted histogram analysis method (WHAM) is routinely used for computing free energies and expectations from multiple ensembles. Existing derivations of WHAM require observations to be discretized into a finite number of bins. Yet, WHAM formulas seem to hold even if the bin sizes are made arbitrarily small.

Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations.

The Binding Energy Distribution Analysis Method (BEDAM) is employed to compute the standard binding free energies of a series of ligands to a FK506 binding protein (FKBP12) with implicit solvation. Binding free energy estimates are in reasonably good agreement with experimental affinities. The conformations of the complexes identified by the simulations are in good agreement with crystallographic data, which was not used to restrain ligand orientations.

The Binding Energy Distribution Analysis Method (BEDAM) for the Estimation of Protein-Ligand Binding Affinities.

The Binding Energy Distribution Analysis Method (BEDAM) for the computation of receptor-ligand standard binding free energies with implicit solvation is presented. The method is based on a well established statistical mechanics theory of molecular association. It is shown that, in the context of implicit solvation, the theory is homologous to the test particle method of solvation thermodynamics with the solute-solvent potential represented by the effective binding energy of the protein-ligand complex.

Antigenic characteristics of rhinovirus chimeras designed in silico for enhanced presentation of HIV-1 gp41 epitopes [corrected].

The development of an effective AIDS vaccine remains the most promising long-term strategy to combat human immunodeficiency virus (HIV)/AIDS. Here, we report favorable antigenic characteristics of vaccine candidates isolated from a combinatorial library of human rhinoviruses displaying the ELDKWA epitope of the gp41 glycoprotein of HIV-1. The design principles of this library emerged from the application of molecular modeling calculations in conjunction with our knowledge of previously obtained ELDKWA-displaying chimeras, including knowledge of a chimera with one of the best 2F5-binding characteristics obtained to date.

In silico vaccine design based on molecular simulations of rhinovirus chimeras presenting HIV-1 gp41 epitopes.

A cluster of promising epitopes for the development of human immunodeficiency virus (HIV) vaccines is located in the membrane-proximal external region (MPER) of the gp41 subunit of the HIV envelope spike structure. The crystal structure of the peptide corresponding to the so-called ELDKWA epitope (HIV-1 HxB2 gp41 residues 662-668), in complex with the corresponding broadly neutralizing human monoclonal antibody 2F5, provides a target for structure-based vaccine design strategies aimed at finding macromolecular carriers that are able to present this MPER-derived epitope with optimal antigenic activity. To this end, a series of replica exchange molecular dynamics computer simulations was conducted to characterize the distributions of conformations of ELDKWA-based epitopes inserted into a rhinovirus carrier and to identify those with the highest fraction of conformations that are able to bind 2F5.