A5038176620- Protein Structure and Dynamics
- Spectroscopy and Quantum Chemical Studies
- Computational Drug Discovery Methods
- Alzheimer's disease research and treatments
- Enzyme Structure and Function
- SARS-CoV-2 and COVID-19 Research
- Parkinson's Disease Mechanisms and Treatments
- Machine Learning in Bioinformatics
- Advanced Chemical Physics Studies
- Microtubule and mitosis dynamics
- Physiological and biochemical adaptations
- Lipid Membrane Structure and Behavior
- Mass Spectrometry Techniques and Applications
- Supramolecular Self-Assembly in Materials
- Bacteriophages and microbial interactions
- Monoclonal and Polyclonal Antibodies Research
- Proteins in Food Systems
- NMR spectroscopy and applications
- biodegradable polymer synthesis and properties
- Photosynthetic Processes and Mechanisms
- Hemoglobin structure and function
- Nanopore and Nanochannel Transport Studies
- Signaling Pathways in Disease
- Electrochemical Analysis and Applications
- Long-Term Effects of COVID-19
Queen's University Belfast
2025
University of Cambridge
2019-2025
Alexander Fleming Biomedical Sciences Research Center
2022-2025
University of Amsterdam
2016-2019
ETH Zurich
2017-2018
Università della Svizzera italiana
2017-2018
Vrije Universiteit Amsterdam
2017-2018
Vitenparken
2018
Abstract Deep learning methods of predicting protein structures have reached an accuracy comparable to that high-resolution experimental methods. It is thus possible generate accurate models the native states hundreds millions proteins. An open question, however, concerns whether these advances can be translated disordered proteins, which should represented as structural ensembles because their heterogeneous and dynamical nature. To address this problem, we introduce AlphaFold-Metainference...
Several human disorders, including Alzheimer’s disease (AD), are characterized by the aberrant formation of amyloid fibrils. In many cases, core is flanked disordered regions, known as fuzzy coat. The structural properties coats, and their interactions with environments, however, have not been fully described to date. Here, we generate conformational ensembles two brain-derived filaments Aβ42, corresponding respectively familial sporadic forms AD. Our approach, called metadynamic electron...
Abstract The phenomenon of protein aggregation is associated with a wide range human diseases. Our knowledge the behaviour viral proteins, however, still rather limited. Here, we investigated this in SARS-CoV and SARS-CoV-2 proteomes. An initial analysis using panel sequence-based predictors suggested presence multiple aggregation-prone regions (APRs) these proteomes revealed strong propensity some proteins. We then studied vitro predicted proteins regions, including signal sequence peptide...
Abstract Machine learning methods hold the promise to reduce costs and failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where development disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine approach identify small molecule inhibitors α-synuclein aggregation, process implicated in Parkinson’s disease other synucleinopathies. Because proliferation aggregates takes...
In the early stages of drug development, large chemical libraries are typically screened to identify compounds promising potency against chosen targets. Often, however, resulting hit tend have poor metabolism and pharmacokinetics (DMPK), with negative developability features that may be difficult eliminate. Therefore, starting discovery process a "null library", highly desirable DMPK properties but no targets, could advantageous. Here, we explore opportunities offered by machine learning...
In computational physics, chemistry, and biology, the implementation of new techniques in shared open-source software lowers barriers to entry promotes rapid scientific progress. However, effectively training users presents several challenges. Common methods like direct knowledge transfer in-person workshops are limited reach comprehensiveness. Furthermore, while COVID-19 pandemic highlighted benefits online training, traditional tutorials can quickly become outdated may not cover all...
The extensive conformational dynamics of partially disordered proteins hinders the efficiency traditional in-silico structure-based drug discovery approaches due to challenge screening large chemical spaces compounds, albeit with an excessive number transient binding sites, quickly making this problem intractable. In study, using monomer AR-V7 transcription factor splicing variant related prostate cancer as a test case, we present deep ensemble docking pipeline that accelerates small...
Elucidation of the ligand/protein binding interaction is paramount relevance in pharmacology to increase success rate drug design. To this end, a number computational methods have been proposed; however all them suffer from limitations since ligand binding/unbinding transitions molecular target involve many slow degrees freedom that hamper full characterization process. Being able express transition simple and general would give distinctive advantage, it require minimal knowledge system...
Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine ensemble conformations representing structure and dynamics tau-microtubule complex comprising entire microtubule-binding region tau (residues 202-395). thus identify ground state series excited states lower populations. A comparison interactions in these different reveals positions along sequence are...
The presence of amyloid fibrils α-synuclein is closely associated with Parkinson's disease and related synucleinopathies. It still very challenging, however, to systematically discover small molecules that prevent the formation these aberrant aggregates. Here, we describe a structure-based approach identify specifically inhibit surface-catalyzed secondary nucleation step in aggregation by binding surface fibrils. resulting are screened using range kinetic thermodynamic assays for their...
Abstract Deep learning methods of predicting protein structures have reached an accuracy comparable to that high-resolution experimental methods. It is thus possible generate accurate models the native states hundreds millions proteins. An open question, however, concerns whether these advances can be translated disordered proteins, which should represented as structural ensembles because their heterogeneous and dynamical nature. Here we show inter-residue distances predicted by AlphaFold...
Camelid single-domain antibodies, also known as nanobodies, can be readily isolated from naïve libraries for specific targets but often bind too weakly to their immediately useful. Laboratory-based genetic engineering methods enhance affinity, termed maturation, deliver useful reagents different areas of biology and potentially medicine. Using the receptor binding domain (RBD) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein a library, we generated closely related...
The high attrition rate in drug discovery pipelines is an especially pressing issue for Parkinson's disease, which no disease-modifying drugs have yet been approved. Numerous clinical trials targeting α-synuclein aggregation failed, at least part due to the challenges identifying potent compounds preclinical investigations. To address this problem, we present a machine learning approach that combines generative modeling and reinforcement identify small molecules perturb kinetics of manner...
In recent years, major advances in cryo-electron microscopy (cryo-EM) have enabled the routine determination of complex biomolecular structures at atomistic resolution. An open challenge for this approach, however, concerns large systems that exhibit continuous dynamics. To address problem, we developed metadynamic electron metainference (MEMMI) method, which incorporates metadynamics, an enhanced conformational sampling into method integrative structural biology. MEMMI enables simultaneous...
As water is an essential ingredient in protein structure, dynamics, and functioning, knowledge of its behavior near proteins crucial. We investigate dynamics around bovine α-lactalbumin by combining molecular simulations with polarization-resolved femtosecond infrared (fs-IR) spectroscopy. identify slowly reorienting surface waters establish their hydrogen-bond lifetime reorientation which we compare to the experimentally measured anisotropy decay. The calculated number slow reasonable...
A structural ensemble derived from cryo-electron microscopy reveals a cryptic pocket site in intermediate states along the opening pathway of SARS-CoV-2 spike protein.
Many processes of scientific importance are characterized by time scales that extend far beyond the reach standard simulation techniques. To circumvent this impediment, a plethora enhanced sampling methods has been developed. One important class such relies on application bias is function set collective variables specially designed for problem under consideration. The design good can be challenging and thereby constitutes main bottle neck in these methods. address problem, recently we have...
We present a novel transition path sampling shooting algorithm for the efficient of complex (biomolecular) activated processes with asymmetric free energy barriers. The method employs fictitious potential that biases point toward state. is similar in spirit to aimless technique by Peters and Trout [J. Chem. Phys. 125, 054108 (2006)], but targeted use one-way approach, which has been shown be more effective than two-way algorithms systems dominated diffusive dynamics. illustrate on 2D...
From the point of view statistical mechanics, a full characterization molecular system requires an accurate determination its possible states, their populations, and respective interconversion rates. Toward this goal, well-established methods increase accuracy dynamics simulations by incorporating experimental information about states using structural restraints populations thermodynamics restraints. However, it is still unclear how to include knowledge Here, we introduce method imposing...
The accurate recapitulation in an vitro assay of the aggregation process α-synuclein Parkinson's disease has been a significant challenge. As does not aggregate spontaneously most currently used assays, primary nucleation is triggered by presence surfaces such as lipid membranes or interfaces created shaking, to achieve on accessible time scales. In addition, secondary typically only observed lowering pH below 5.8. Here we investigated conditions that enables spontaneous and at 7.4. Using...
Empirical force fields employed in molecular dynamics simulations of complex systems are often optimized to reproduce experimentally determined structural and thermodynamic properties. In contrast, experimental knowledge about the interconversion rates between metastable states such is hardly ever incorporated a field due lack an efficient approach. Here, we introduce framework based on relationship dynamical observables, as rate constants, underlying model parameters using statistical...
Misfolded protein oligomers are of central importance in both the diagnosis and treatment Alzheimer's Parkinson's diseases. However, accurate high-throughput methods to detect quantify oligomer populations still needed. We present here a single-molecule approach for detection quantification oligomeric species. The is based on use solid-state nanopores multiplexed DNA barcoding identify characterize from multiple samples. study α-synuclein presence several small-molecule inhibitors...
Abstract Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present multidisciplinary lead discovery approach identify optimize small molecule inhibitors pathogenic fibroblast activation. The study encompasses medicinal chemistry, molecular phenotyping assays, chemoproteomics, bulk RNA‐sequencing analysis, target validation experiments, chemical...
The aggregation of tau into amyloid fibrils is associated with Alzheimer's disease (AD) and related tauopathies. Since different tauopathies are characterised by the formation distinct fibril morphologies, it important to combine search inhibitors development in vitro assays that recapitulate as may occur brain. Here we address this problem reporting an assay which AD brain homogenates used seed generation first-generation a polymorph-specific manner under quiescent conditions. These then...
Transition path sampling is a powerful technique for investigating rare transitions, especially when the mechanism unknown and one does not have access to reaction coordinate. Straightforward application of transition directly provide free energy landscape nor kinetics. This drawback has motivated development extensions able simultaneously both kinetics thermodynamics, such as interface sampling, reweighted ensemble. However, performing more involved than standard two-state still requires...