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Publications (45)
A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase-separated molecular 'sponges', stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self...
A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase-separated molecular 'sponges', stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self...
Lack of effective strategies for killing cells latently infected with HIV-1 limits the eradication of AIDS. Unfortunately, current antiretroviral inhibitors are designed to target virus production but not latent infection. Interestingly, some non-nucleoside reverse-transcriptase inhibitors (NNRTIs) have shown off-design effects, specifically, prema...
Cell motility is essential for protozoan and metazoan organisms and typically relies on the dynamic turnover of actin filaments. In metazoans, monomeric actin polymerises into usually long and stable filaments, while some protozoans form only short and highly dynamic actin filaments. These different dynamics are partly due to the different sets of...
Soraphen A is a myxobacterial metabolite that blocks the acetyl-CoA carboxylase of the host, and was previously identified as a novel HIV inhibitor. Here we report that Soraphen A acts by reducing virus production and altering the gp120 virion content, impacting entry capacity and infectivity. These effects are partially reversed by addition of pal...
A considerable number of approved drugs show non-equilibrium binding characteristics, emphasizing the potential role of drug residence times for in vivo efficacy. Therefore, a detailed understanding of the kinetics of association and dissociation of a target–ligand complex might provide crucial insight into the molecular mechanism-of-action of a co...
Retrovirus particle (virion) infectivity requires diffusion and clustering of multiple transmembrane envelope proteins (Env 3 ) on the virion exterior, yet is triggered by protease-dependent degradation of a partially occluding, membrane-bound Gag polyprotein lattice on the virion interior. The physical mechanism underlying such coupling is unclear...
Near attack conformations (NACs) are conformations extending from the ground state (GS) that lie on the transition path of a chemical reaction. Here, we develop a method for computing the thermodynamic contribution to catalysis due to NAC formation in bimolecular reactions, within the limit of a classical molecular dynamics force field. We make use...
The distribution of virion maturation times from 10,000 simulations with random parameter sets.
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Adding an initial inoculum of mature protease results in modest decrease in VMT.
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The time course of simulated Gag and Gag-Pol processing, using kinetic rate constants estimated based on full-length Gag cleavage. (A) Virus maturation time (VMT) (dashed red line in all panels) is still triggered by the decay of the CA.SP1 fragment (blue line; threshold of trans-dominant inhibition of particle maturation indicated by dashed horizo...
Estimation of catalytic rate constants.
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The effect of single parameter variation on VMT using an alternative set of kinetic rate constants.
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The time course of the major intermediates of simulated Gag (A) and Gag-Pol (B) processing.
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Compensation of virion maturation time (VMT) with different time courses of reaction products.
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Half-normalized local sensitivity functions of the concentration of CA.SP1 with respect to selected parameters.
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Computer code of simulations.
(ZIP)
The size of the critical subset of PR or Gag-Pol dimers as a function of VMT required for viability. Simulations were run with different concentrations of two types of inhibitors binding either to mature PR (red symbols) or to full-length Gag-Pol dimers (blue symbols). The binding rate constants of both PIs were parameterized with data estimated fo...
The conformationally flexible fusion peptide (FP) of HIV-1 is indispensible for viral infection of host cells, due to its ability to insert into and tightly couple with phospholipid membranes. There are conflicting reports on the membrane-associated structure of FP, and solution structure information is limited, yet such a structure is the target f...
Proteolytic processing of Gag and Gag-Pol polyproteins by the viral protease (PR) is crucial for the production of infectious HIV-1, and inhibitors of the viral PR are an integral part of current antiretroviral therapy. The process has several layers of complexity (multiple cleavage sites and substrates; multiple enzyme forms; PR auto-processing),...
HIV maturation requires multiple cleavage of long polyprotein chains into functional proteins that include the viral protease itself. Initial cleavage by the protease dimer occurs from within these precursors, and yet only a single protease monomer is embedded in each polyprotein chain. Self-activation has been proposed to start from a partially di...
Functioning of G protein-coupled receptors (GPCRs) is tightly linked to the membrane environment, but a molecular level understanding of the modulation of GPCR by membrane lipids is not available. However, specific receptor-lipid interactions as well as unspecific effects mediated by the bulk properties of the membrane (thickness, curvature, etc.)...
One of the principal targets in human immunodeficiency virus type 1 (HIV-1) therapy is the reverse transcriptase (RT) enzyme. Non-nucleoside RT inhibitors (NNRTIs) are a class of highly specific drugs which bind to a pocket approximately 10 Å from the polymerase active site, inhibiting the enzyme allosterically. It is widely believed that NNRTIs fu...
The nuclear receptor superfamily (NRs) comprises ligand-dependent transcription regulators, many of which function as homodimers or heterodimers with RXR. We show that addition of an SRC-1 coactivator-derived peptide to mo-nomeric liganded retinoic acid receptor (RAR) promotes efficient homodimer formation. X-ray crystallography revealed that homod...
A theoretical formulation for complete heteropolymer degradation is developed in terms of Michaelis-Menten reaction kinetics under the quasi-steady-state approximation. This allows the concentration of the entire intermediate decomposition cascade to be accounted for as well as each species of emerging final product. The formulation is implemented...
The prediction of protein–ligand binding free energies is an important goal of computational biochemistry, yet accuracy, reproducibility, and cost remain a problem. Nevertheless, these are essential requirements for computational methods to become standard binding prediction tools in discovery pipelines. Here, we present the results of an extensive...
An accurate description of the conformational dynamics of the β-hairpin flaps of HIV-1 protease is of central importance in elucidating the functional recognition of the enzyme by ligands. Using all-atom molecular dynamics simulations in explicit solvent, with a total of 461 trajectories of ∼50 ns each, we report the closed, semiopen, open, and wid...
Accurate calculation of important thermodynamic properties, such as macromolecular binding free energies, is one of the principal goals of molecular dynamics simulations. However, single long simulation frequently produces incorrectly converged quantitative results due to inadequate sampling of conformational space in a feasible wall-clock time. Mu...
Medical practitioners have limited ways of matching a drug to the unique genetic profile of a virus population as it mutates within a patient under drug-related selective pressure. Currently, knowledge based decision support software based on existing clinical records and associated viral genotypic data is used to aid inhibitor selection. In the in...
We describe computational science research that uses petascale resources to achieve scientific results at unprecedented scales and resolution. The applications span a wide range of domains, from investigation of fundamental problems in turbulence through computational materials science research to biomedical applications at the forefront of HIV/AID...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The successful application of high throughput molecular simulations to determine biochemical properties would be of great importance to the biomedical community if such simulations could be turned around in a clinically relevant timescale. An important example is the determination of antiretroviral inhibitor efficacy against varying strains of HIV...
The clinical management of HIV-positive patients receiving existing drug regimens is performed largely as a clinician's best guess, based on available viral and patient data. The development of new antiretroviral therapies for HIV is at an impasse. How can we progress beyond this? ViroLab, an example of a new 'style' of research project, is attempt...
Patient-specific medical simulation holds the promise of determining tailored medical treatment based on the characteristics of an individual patient (for example, using a genotypic assay of a sequence of DNA). Decision-support systems based on patient-specific simulation can potentially revolutionize the way that clinicians plan courses of treatme...
To explain drug resistance by computer simulations at the molecular level, we first have to assess the accuracy of theoretical predictions. Herein we report an application of the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) technique to the ranking of binding affinities of the inhibitor saquinavir with the wild type (WT) and three r...
Overcoming the emergence of drug resistance in HIV is a major challenge to the scientific community. We use the established computational method of classical molecular dynamics to investigate the molecular basis of resistance in HIV-1 protease to the inhibitor saquinavir, using the wildtype and the G48V, L90M and G48V7L90M mutant HIV-1 proteases th...
We provide insight into the first stages of a kinetic mechanism of lateral drug expulsion from the active site of HIV-1 protease, by conducting all atom molecular dynamics simulations with explicit solvent over a time scale of 24 ns for saquinavir bound to the wildtype, G48V, L90M and G48V/L90M mutant proteases. We find a consistent escape mechanis...
Drug resistant mutations have severely limited the success of HIV therapy. Here we provide insight into the molecular basis
of drug resistance in HIV-1 protease with the inhibitor saquinavir. We employ protocols consisting of chained molecular dynamics
simulations that allow preparation of desired mutants from an available wildtype structure. By co...
Current grid computing (1, 2) technologies have often been seen as being too heavyweight and unwieldy from a client perspective, requiring complicated installation and configuration steps to be taken that are beyond the ability of most end users. This has led many of the people who would benefit most from grid technology, namely application scienti...
Many crystal structures of HIV-1 protease exist, but the number of clinically interesting drug resistant mutational patterns is far larger than the available crystal structures. Muta- tional protocols convert one protease sequence with available crystal structure into another that diverges by a small number of mutations. It is important that such m...
