A5033516543- HIV Research and Treatment
- Protein Structure and Dynamics
- HIV/AIDS drug development and treatment
- DNA and Nucleic Acid Chemistry
- Click Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- Distributed and Parallel Computing Systems
- Receptor Mechanisms and Signaling
- Chemical Reactions and Isotopes
- Bacteriophages and microbial interactions
- RNA and protein synthesis mechanisms
- Scientific Computing and Data Management
- HIV/AIDS Research and Interventions
- Advanced Data Storage Technologies
- RNA modifications and cancer
- RNA Research and Splicing
- Machine Learning in Bioinformatics
- Chemical Synthesis and Analysis
- SARS-CoV-2 and COVID-19 Research
- Synthesis and biological activity
- Glycosylation and Glycoproteins Research
- Platelet Disorders and Treatments
- Hepatitis C virus research
- Malaria Research and Control
Heidelberg Institute for Theoretical Studies
2016-2023
European Molecular Biology Laboratory
2021
Universitat Pompeu Fabra
2011-2021
Barcelona Biomedical Research Park
2010-2021
European Molecular Biology Laboratory
2019-2021
Municipal Institute for Medical Research
2012
University College London
2006-2010
To explain drug resistance by computer simulations at the molecular level, we first have to assess accuracy of theoretical predictions. Herein report an application mechanics Poisson−Boltzmann surface area (MM/PBSA) technique ranking binding affinities inhibitor saquinavir with wild type (WT) and three resistant mutants HIV-1 protease: L90M, G48V, G48V/L90M. For each ligand−protein complex 10 ns fully unrestrained dynamics (MD) explicit solvent. We investigate convergence, internal...
De novo protein design is a longstanding fundamental goal of synthetic biology, but has been hindered by the difficulty in reliable prediction accurate high-resolution structures from sequence. Recent advances accuracy structure methods, such as AlphaFold (AF), have facilitated proteome scale structural predictions monomeric proteins. Here we develop AlphaDesign, computational framework for de that embeds AF an oracle within optimisable process. Our enables rapid completely novel monomers...
HIV maturation requires multiple cleavage of long polyprotein chains into functional proteins that include the viral protease itself. Initial by dimer occurs from within these precursors, and yet only a single monomer is embedded in each chain. Self-activation has been proposed to start partially dimerized formed monomers different binding its own N termini self-association active site, but complete structural understanding this critical step missing. Here, we captured immature HIV-1...
Accurate calculation of important thermodynamic properties, such as macromolecular binding free energies, is one the principal goals molecular dynamics simulations. However, single long simulation frequently produces incorrectly converged quantitative results due to inadequate sampling conformational space in a feasible wall-clock time. Multiple short (ensemble) simulations have been shown explore more effectively than simulations, but two methods not yet thermodynamically compared. Here we...
Proteolytic processing of Gag and Gag-Pol polyproteins by the viral protease (PR) is crucial for production infectious HIV-1, inhibitors PR are an integral part current antiretroviral therapy. The process has several layers complexity (multiple cleavage sites substrates; multiple enzyme forms; auto-processing), which calls a systems level approach to identify key vulnerabilities optimal treatment strategies. Here we present first full reaction kinetics model proteolytic HIV-1 PR, taking into...
Cell motility is essential for protozoan and metazoan organisms typically relies on the dynamic turnover of actin filaments. In metazoans, monomeric polymerises into usually long stable filaments, while some protozoans form only short highly These different dynamics are partly due to sets regulatory proteins sequence itself. Here we probe interactions subunits within divergent filaments using a comparative molecular model explore their functions Plasmodium, causing malaria, mouse melanoma...
The successful application of high throughput molecular simulations to determine biochemical properties would be great importance the biomedical community if such could turned around in a clinically relevant timescale. An important example is determination antiretroviral inhibitor efficacy against varying strains HIV through calculation drug−protein binding affinities. We describe Binding Affinity Calculator (BAC), tool for automated HIV-1 protease−ligand employs fully atomistic alongside...
An accurate description of the conformational dynamics β-hairpin flaps HIV-1 protease is central importance in elucidating functional recognition enzyme by ligands. Using all-atom molecular simulations explicit solvent, with a total 461 trajectories ∼50 ns each, we report closed, semiopen, open, and wide-open flap conformation free wild-type protease. The energy opening closing from semiopen state 0.9 ± 0.2 2.4 0.4 kcal/mol, respectively. mean relaxation time ∼8 ns, good agreement NMR data....
Near attack conformations (NACs) are extending from the ground state (GS) that lie on transition path of a chemical reaction. Here, we develop method for computing thermodynamic contribution to catalysis due NAC formation in bimolecular reactions, within limit classical molecular dynamics force field. We make use Bürgi–Dunitz theory applied large-scale unbiased all-atom ensemble simulations. apply this HIV-1 protease peptide hydrolysis, known achieve rate enhancement ∼1011 (ΔGcat⧧ ∼ 15...
The prediction of protein-ligand binding free energies is an important goal computational biochemistry, yet accuracy, reproducibility, and cost remain a problem. Nevertheless, these are essential requirements for methods to become standard tools in discovery pipelines. Here, we present the results extensive search optimal method based on ensemble umbrella sampling all-atom molecular simulations tested phosphorylated tetrapeptide, pYEEI, SH2 domain, resulting accurate converged energy -9.0 ±...
The COVID-19 pandemic continues to pose a substantial threat human lives and is likely do so for years come. Despite the availability of vaccines, searching efficient small-molecule drugs that are widely available, including in low- middle-income countries, an ongoing challenge. In this work, we report results open science community effort, "Billion molecules against challenge", identify inhibitors SARS-CoV-2 or relevant receptors. Participating teams used wide variety computational methods...
Patient-specific medical simulation holds the promise of determining tailored treatment based on characteristics an individual patient (for example, using a genotypic assay sequence DNA). Decision-support systems patient-specific can potentially revolutionize way that clinicians plan courses for various conditions, ranging from viral infections to arterial abnormalities. Basing decisions results simulations use models derived data specific in question means effectiveness range potential...
Functioning of G protein-coupled receptors (GPCRs) is tightly linked to the membrane environment, but a molecular level understanding modulation GPCR by lipids not available. However, specific receptor-lipid interactions as well unspecific effects mediated bulk properties (thickness, curvature, etc.) have been proposed be key regulators modulation. In this review, we examine computational efforts made towards modeling and simulation (i) complex behavior lipids, (ii) lipid-GPCR lipid-mediated...
We provide insight into the first stages of a kinetic mechanism lateral drug expulsion from active site HIV-1 protease, by conducting all atom molecular dynamics simulations with explicit solvent over time scale 24 ns for saquinavir bound to wildtype, G48V, L90M and G48V/L90M mutant proteases. find consistent escape associated G48V mutation. First, increased hydrophilic hydrophobic flap coupling water mediated disruption catalytic dyad hydrogen bonding induce motion away promote protease...
One of the principal targets in human immunodeficiency virus type 1 (HIV-1) therapy is reverse transcriptase (RT) enzyme. Non-nucleoside RT inhibitors (NNRTIs) are a class highly specific drugs which bind to pocket approximately 10 Å from polymerase active site, inhibiting enzyme allosterically. It widely believed that NNRTIs function as "molecular wedges", disrupting region between thumb and palm subdomains p66 subunit locking wide-open conformation. Crystal structure data suggest binding...
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 fundamental problems in turbulence through materials biomedical the forefront HIV/AIDS cerebrovascular haemodynamics. This work was mainly performed on US TeraGrid 'petascale' resource, Ranger, Texas Advanced Computing Center, first half 2008 when it largest computing system world...
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 quinary (transient weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form self-assembly when their genomic RNA (gRNA) traps Gag GagPol polyprotein precursors. Infectivity requires extracellular budding the particle followed...
The conformationally flexible fusion peptide (FP) of HIV-1 is indispensible for viral infection host cells, due to its ability insert into and tightly couple with phospholipid membranes. There are conflicting reports on the membrane-associated structure FP, solution information limited, yet such a target novel class antiretroviral inhibitors. An ensemble explicit solvent molecular dynamics simulations, initiated from disordered FP (aggregate time ∼30 μs), revealed that while vast majority...
Elucidation and improvement of the blood coagulant properties heparin are focus intense research. In this study, we performed conformational analysis using nuclear magnetic resonance (NMR) spectroscopy molecular dynamics (MD) simulations on pentasaccharide analogue idraparinux, its disulfonatomethyl analogue, which features a slightly improved coagulation property, trisulfonatomethyl in activity has been totally abolished. As ring conformation G subunit suggested as major determinant...
A theoretical formulation for complete heteropolymer degradation is developed in terms of Michaelis-Menten reaction kinetics under the quasi-steady-state approximation. This allows concentration entire intermediate decomposition cascade to be accounted as well each species emerging final product. The implemented computationally and results stable across a range orders magnitude K(M) k(cat). model compared with experiment, specifically vitro HIV-1 protease-catalyzed retroviral Gag-polyprotein...
Soraphen A is a myxobacterial metabolite that blocks the acetyl-coenzyme carboxylase of host and was previously identified as novel HIV inhibitor. Here, we report soraphen acts by reducing virus production altering gp120 virion content, impacting entry capacity infectivity. These effects are partially reversed addition palmitic acid, suggesting inhibition envelope palmitoylation one mechanisms antiviral action.
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 a partially occluding, membrane-bound Gag polyprotein lattice interior. The physical mechanism underlying such coupling unclear only indirectly accessible via experiment. Modelling stands to provide insight but required spatio-temporal range far exceeds current accessibility all-atom or even...
We develop an approach to characterize the effects of gating by a multiconformation protein consisting macrostate conformations that are either accessible or inaccessible ligand binding. first construct Markov state model apo-protein from atomistic molecular dynamics simulations which we identify macrostates and their conformations, compute relative populations interchange kinetics, structurally them in terms accessibility. insert calculated first-order rate constants for conformational...