A5064391171- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Heat shock proteins research
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- thermodynamics and calorimetric analyses
- Mass Spectrometry Techniques and Applications
- Lipid Membrane Structure and Behavior
- Analytical Chemistry and Chromatography
- Alzheimer's disease research and treatments
- Distributed and Parallel Computing Systems
- Spectroscopy and Quantum Chemical Studies
- Photosynthetic Processes and Mechanisms
- HIV/AIDS drug development and treatment
- Supramolecular Self-Assembly in Materials
- Genetics, Bioinformatics, and Biomedical Research
- Photoreceptor and optogenetics research
- Chemical Synthesis and Analysis
- Scientific Computing and Data Management
- SARS-CoV-2 and COVID-19 Research
- DNA and Nucleic Acid Chemistry
- Glycosylation and Glycoproteins Research
- Endoplasmic Reticulum Stress and Disease
National Research Council
2012-2024
Cornell University
2014-2023
Weill Cornell Medicine
2022-2023
Istituto di Scienze e Tecnologie Chimiche "Giulio Natta"
2021
Istituto di Nanotecnologia
2020
Institute of Chemistry of Molecular Recognition
2010-2020
Mylan (South Africa)
2020
National Academies of Sciences, Engineering, and Medicine
2012
University of Massachusetts Chan Medical School
2010
National Cancer Institute
2010
Hsp90 is a molecular chaperone essential for protein folding and activation in normal homeostasis stress response. ATP binding hydrolysis facilitate conformational changes required client activation. plays an important role disease states, particularly cancer, where chaperoning of the mutated overexpressed oncoproteins function. Recent studies have illuminated mechanisms related to However, atomic resolution view dynamics, determined by presence different partners, critical define...
Understanding how local protein modifications, such as binding small-molecule ligands, can trigger and regulate large-scale motions of large domains is a major open issue in molecular biology. We address various aspects this problem by analyzing comparing atomistic simulations Hsp90 family representatives for which crystal structures the full length are available: mammalian Grp94, yeast E.coli HtpG. These chaperones studied complex with natural ligands ATP, ADP Apo state. Common key their...
G protein-coupled receptors (GPCRs) play a key role in many cellular signaling mechanisms, and must select among multiple coupling possibilities ligand-specific manner order to carry out myriad of functions diverse contexts. Much has been learned about the molecular mechanisms ligand-GPCR complexes from Molecular Dynamics (MD) simulations. However, explore differences response GPCR ligands, as is required understand ligand bias functional selectivity, necessitates creating very large amounts...
The study of allosteric functional modulation in dynamic proteins is attracting increasing attention. In particular, the discovery new sites may generate novel opportunities and strategies for drug development, overcoming limits classical active-site oriented design. this paper, we report on results a novel, ab initio, fully computational approach inhibitors based physical characterization signal propagation mechanisms apply it to important molecular chaperone Hsp90. We first characterize...
Molecular switching and ligand-based modulation of the 90-kDa heat-shock protein (Hsp90) chaperone activity may ultimately facilitate conformational coupling to ATPase cycle along with activation recruitment broad range client proteins. We present an atomic resolution analysis Hsp90 N-terminal domain (NTD) binding energy landscape by simulating dynamics a partners. show that molecular be linked (i) local folding-unfolding transitions "active site lid" upon (ii) differences in underlying as...
SARS-CoV-2 is a health threat with dire socioeconomical consequences. As the crucial mediator of infection, viral glycosylated spike protein (S) has attracted most attention and at center efforts to develop therapeutics diagnostics. Herein, we use an original decomposition approach identify energetically uncoupled substructures as antibody binding sites on fully S. Crucially, all that required are unbiased MD simulations; no prior knowledge properties or ad hoc parameter combinations needed....
Abstract Most proteins must fold to a well‐defined structure with minimal stability perform their function. Here we use simple, molecular dynamics‐based, energy decomposition approach map the principal energetic interactions in set of representative different folds. This work involves all‐atom simulation and analysis native structures mutants five an all‐alpha (yACPB, Protein A), all‐beta (SH3), mixed α/β (Proteins G L). Given certain structure, sequence mutants, show that our model...
Background The conversion of the cellular prion protein (PrPC) into infectious form (PrPSc) is key event in induced neurodegenerations. This process believed to involve a multi-step conformational transition from an α-helical β-sheet-rich state. In addition difference, PrPSc exhibits as covalent signature sulfoxidation M213. To investigate whether such modification may play role misfolding we have studied impact methionine oxidation on dynamics and energetics HuPrP(125–229) α-fold....
Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition Substrate (SBD). Herein, a comparative analysis (Hsp70-DnaK) non-allosteric structural homolog (Hsp110-Sse1) carried out through molecular dynamics simulations, starting from different conformations...
Allostery is a general phenomenon in proteins whereby perturbation at one site reverberates into functional change another one, through modulation of its conformational dynamics. Herein, we address the problem how molecular signal encoded by ligand differentially transmitted structures two homologous PDZ proteins: PDZ2, which responds to binding with structural and dynamical changes regions distal from site, PDZ3, characterized less-intense variations. We use novel methods analysis MD...
The subdivision of protein structures into smaller and independent structural domains has a fundamental importance in understanding evolution function the development classification methods as well interpretation experimental data. Due to rapid growth number solved structures, need for devising new accurate algorithmic become more urgent. In this paper, we propose computational approach that is based on concept domain compact folding unit analysis residue–residue energy interactions...
Abstract The Hsp70 is an allosterically regulated family of molecular chaperones. They consist two structural domains, NBD and SBD, connected by a flexible linker. ATP hydrolysis at the modulates substrate recognition while peptide binding SBD enhances hydrolysis. In this study we apply Molecular Dynamics (MD) to elucidate determinants underlying allosteric communication from back. We observe that local dynamical modulation can be coupled large-scale rearrangements, different combinations...
Although intensively studied, the high-resolution crystal structure of peptide DFNKF, core-segment human calcitonin, has never been described. Here we report how use iodination as a strategy to promote crystallisation and facilitate phase determination, allowed us solve, for first time, single-crystal X-ray DFNKF derivative. Computational studies suggest that both iodinated wild-type peptides populate very similar conformations. Furthermore, conformer found in solid-state is one most...
The absolute values of the one-electron redox potentials two quinones (QA and QB) in bacterial photosynthetic reaction centers from Rhodobacter sphaeroides were calculated by evaluating electrostatic energies solution linearized Poisson−Boltzmann equation at pH 7.0. potential for QA was to be between −173 −160 mV, which is close lowest measured that are assumed refer nonequilibrated protonation patterns state QA-. quinone QB found about 160−220 mV larger light-exposed than dark-adapted...
Herein we investigate the potential of novel methods molecular dynamics analysis to provide information on key factors that underlie preferential localization and effects mutations modulating protein activities. Epidermal growth factor receptor (EGFR) kinases are selected as a test case. The combined energetics internal indicates clear polarization in native protein, whereby highly stable ordered scaffold one domain, namely C-lobe, is flexible loosely stabilized N-lobe. subdivision two...
Proteins in the arrestin family exhibit a conserved structural fold that nevertheless allows for significant differences their selectivity G-protein coupled receptors (GPCRs) and phosphorylation states. To reveal mechanism of activation prepares selective interaction with GPCRs, to understand basis these differences, we used unbiased molecular dynamics simulations compare dynamic properties wild type Arr1 (Arr1-WT), Arr3 (Arr3-WT), constitutively active mutant, Arr1-R175E, characterized by...
Dominant negative mutants are useful tools in chemical biology, but they do not mimic the action of allosteric inhibitors. We show that properly-placed tryptophan residues can sometimes be superior for this purpose.