A5000379524- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Protein purification and stability
- Glycosylation and Glycoproteins Research
- Enzyme Structure and Function
- Machine Learning in Materials Science
- Hydrogels: synthesis, properties, applications
- Mosquito-borne diseases and control
- Free Radicals and Antioxidants
- Biochemical Acid Research Studies
- Mass Spectrometry Techniques and Applications
- Advanced Biosensing Techniques and Applications
- Toxin Mechanisms and Immunotoxins
- Computational Drug Discovery Methods
- CAR-T cell therapy research
- Malaria Research and Control
- Spectroscopy and Quantum Chemical Studies
- T-cell and B-cell Immunology
- Advanced Polymer Synthesis and Characterization
- Complement system in diseases
- Machine Learning in Bioinformatics
- Endoplasmic Reticulum Stress and Disease
- Crystallography and molecular interactions
- Galectins and Cancer Biology
- vaccines and immunoinformatics approaches
Scripps Institution of Oceanography
2025
Scripps Research Institute
2023-2024
Universität Innsbruck
2016-2024
We present an approach to assess antibody CDR-H3 loops according their dynamic properties using molecular dynamics simulations. selected six antibodies in three pairs differing substantially individual promiscuity respectively specificity. For two of crystal structures are available different states maturation and used as starting for the analyses. a third pair we chose CDR sequences obtained from synthetic library predicted respective structures. all performed metadynamics simulations...
Protein folding is a fascinating, not fully understood phenomenon in biology. Molecular dynamics (MD) simulations are an invaluable tool to study conformational changes atomistic detail, including and unfolding processes of proteins. However, the accuracy ensembles derived from MD inevitably relies on quality underlying force field combination with respective water model. Here, we investigate protein folding, unfolding, misfolding fast-folding proteins by examining different fields their...
Thermosensitive polymers such as poly(N-isopropylacrylamide) (PNIPAM) undergo a phase transition in aqueous solution from random-coil structural ensemble to globule at the lower critical temperature (LCST). Above this temperature, PNIPAM agglomerates and becomes insoluble, whereas it is soluble below temperature. Thus, thermosensitive represent essential targets for several applications, e.g., drug delivery. Although their ability change structure response alteration highly relevant...
During the affinity maturation process immune system produces antibodies with higher specificity and activity through various rounds of somatic hypermutations in response to an antigen. Elucidating is fundamental understanding immunity development biotherapeutics. Therefore, we analyzed 10 pairs antibody fragments differing their distinct stages using metadynamics combination molecular dynamics (MD) simulations. We investigated differences flexibility CDR-H3 loop global changes plasticity...
Abstract Plasmodium falciparum pathology is driven by the accumulation of parasite-infected erythrocytes in microvessels. This process mediated parasite’s polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. A subset PfEMP1 variants that bind human endothelial C receptor (EPCR) through their CIDRα1 domains responsible for severe malaria pathogenesis. longstanding question whether individual antibodies can recognize large repertoire circulating variants. Here, we describe...
T-cell receptors are an important part in the adaptive immune system as they responsible for detecting foreign proteins presented by major histocompatibility complex (MHC). The affinity is predominantly determined structure and sequence of complementarity determining regions (CDRs), which CDR3 loops peptide recognition. We present a kinetic classification receptor with different loop lengths into canonical non-canonical solution structures. Using molecular dynamics simulations, we do not...
Antibodies have emerged as one of the fastest growing classes biotherapeutic proteins. To improve rational design antibodies, we investigate conformational diversity 16 different germline combinations, which are composed 4 kappa light chains paired with heavy chains. In this study, systematically show that and chain pairings strongly influence paratope, interdomain interaction patterns relative VH-VL interface orientations. We observe changes in substantial population shifts complementarity...
Recycling IgG antibodies bind to their target antigen at physiological pH in the blood stream and release them upon endocytosis when levels drop, allowing be recycled into circulation via FcRn-mediated cellular pathways, while antigens undergo lysosomal degradation. This enables recycling achieve comparable therapeutic effect lower doses than non-recycling counterparts. The development of such is typically achieved by histidine doping variable regions or performing vitro antibody selection...
The electrostatic properties of proteins arise from the number and distribution polar charged residues. Electrostatic interactions in play a critical role numerous processes such as molecular recognition, protein solubility, viscosity, antibody developability. Thus, characterizing quantifying are prerequisites for understanding these processes. Here, we present PEP-Patch, tool to visualize quantify potential on surface terms patches, denoting separated areas with common physical property. We...
The humanization of camelid-derived variable domain heavy chain antibodies (VHHs) poses challenges including immunogenicity, stability, and potential reduction affinity. Critical to this process are complementarity-determining regions (CDRs), Vernier Hallmark residues, shaping the three-dimensional fold influencing VHH structure function. Additionally, presence non-canonical disulfide bonds further contributes conformational stability antigen binding. In study, we systematically humanized...
Many proteins are highly flexible and their ability to adapt shape can be fundamental functional properties. We now computationally predict a single, static protein structure with high accuracy. However, we not yet able reliably structural flexibility. A major factor limiting such predictions is the scarcity of suitable training data. Here, focus on predicting flexibility functionally important antibody T-cell receptor CDR3 loops. extracted dataset like loop motifs from PDB create...
Abstract Antibodies have the ability to bind various types of antigens and recognize different antibody-binding sites (epitopes) same antigen with binding affinities. Due conserved structural framework antibodies, their specificity is mainly determined by antigen-binding site (paratope). Therefore, characterization epitopes in combination describing involved conformational changes paratope upon crucial understanding predicting antibody-antigen binding. Using molecular dynamics simulations...
Fab consist of a heavy and light chain can be subdivided into variable (V H V L ) constant region (C 1 C ). The contains the complementarity-determining (CDR), which is formed by six hypervariable loops, shaping antigen binding site, paratope. Apart from CDR both elbow angle relative interdomain orientations –V 1–C domains influence shape Thus, characterization interface dynamics essential to specificity. We studied nine antigen-binding fragments (Fab) investigate affinity maturation,...
Sequence and structural diversity of antibodies are concentrated on six hypervariable loops, also known as the complementarity determining regions (CDRs). Five antibody CDR loops presumably adopt a so-called canonical structure out limited number conformations. However, here we show for four CDR-L3 differing in length sequence, that each loop undergoes conformational transitions between different structures. By extensive sampling combination with Markov-state models reconstruct kinetics...
Whereas enzymes in the fumarylacetoacetate hydrolase (FAH) superfamily catalyze several distinct chemical reactions, structural basis for their multi-functionality remains elusive. As a well-studied example, human FAH domain-containing protein 1 (FAHD1) is mitochondrial displaying both acylpyruvate (ApH) and oxaloacetate decarboxylase (ODx) activity. ODx, FAHD1 acts antagonistically to pyruvate carboxylase, key metabolic enzyme. Despite its importance function, very little known about...
To characterize the thermosensitive coil–globule transition in atomistic detail, conformational dynamics of linear polymer chains acrylamide-based polymers have been investigated at multiple temperatures. Therefore, molecular dynamic simulations 30mers polyacrylamide (AAm), poly-N-methylacrylamide (NMAAm), poly-N-ethylacrylamide (NEAAm), and poly-N-isopropylacrylamide (NIPAAm) performed temperatures ranging from 250 to 360 K for 2 μs. While two are known exhibit thermosensitivity (NEAAm,...
Hydration thermodynamics play a fundamental role in fields ranging from the pharmaceutical industry to environmental research. Numerous methods exist predict solvation of compounds small molecules large biomolecules. Arguably most precise are those based on molecular dynamics (MD) simulations explicit solvent. One theory that has seen increased use is inhomogeneous (IST). However, while many applications require accurate description salt-water mixtures, no implementation IST currently able...
Hydration is one of the key players in protein-ligand binding process. It not only influences process per se, but also drug's absorption, distribution, metabolism, and excretion properties. To gain insights into hydration aromatic cores, solvation thermodynamics 40 mono- bicyclic systems, frequently occurring medicinal chemistry, are investigated. Thermodynamics analyzed with two different methods: grid inhomogeneous theory (GIST) thermodynamic integration (TI). Our results agree well...
The use of fragments to biophysically characterize a protein binding pocket and determine the strengths certain interactions is computationally experimentally commonly applied approach. Almost all drug like molecules contain at least one aromatic moiety forming stacking in pocket. In computational design, strength resulting optimization core or usually calculated using high level quantum mechanical approaches. However, as these calculations are performed vacuum, solvation properties...