Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β.
PNAS 113(33):E4801 (2016)
Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expr...
Strain Mediated Adaptation Is Key for Myosin Mechanochemistry: Discovering General Rules for Motor Activity.
PLoS computational biology 12(8):e1005035 (2016)
A structure-based model of myosin motor is built in the same spirit of our early work for kinesin-1 and Ncd towards physical understanding of its mechanochemical cycle. We find a structural adaptation of the motor head domain in post-powerstroke state that signals faster ADP release from it comp...
Information and redundancy in the burial folding code of globular proteins within a wide range of shapes and sizes.
Proteins: Structure, Function and Bioinformatics 84(4):515 (2016)
Recent ab initio folding simulations for a limited number of small proteins have corroborated a previous suggestion that atomic burial information obtainable from sequence could be sufficient for tertiary structure determination when combined to sequence-independent geometrical constraints. Here...
SMOG 2: A Versatile Software Package for Generating Structure-Based Models.
PLoS computational biology 12(3):e1004794 (2016)
Molecular dynamics simulations with coarse-grained or simplified Hamiltonians have proven to be an effective means of capturing the functionally important long-time and large-length scale motions of proteins and RNAs. Originally developed in the context of protein folding, structure-based models...
Constructing sequence-dependent protein models using coevolutionary information.
Protein Science 25(1):111 (2016)
Recent developments in global statistical methodologies have advanced the analysis of large collections of protein sequences for coevolutionary information. Coevolution between amino acids in a protein arises from compensatory mutations that are needed to maintain the stability or function of a ...
Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells.
Journal of Cell Science 129(1):155 (2016)
Maintaining iron (Fe) ion and reactive oxygen species homeostasis is essential for cellular function, mitochondrial integrity and the regulation of cell death pathways, and is recognized as a key process underlying the molecular basis of aging and various diseases, such as diabetes, neurodegener...
Preface to Special Topic on Protein Dynamics: Beyond Static Snapshots in Structural Biology.
Structural Dynamics 3(1):011901 (2016)
Periodic, Quasi-periodic and Chaotic Dynamics in Simple Gene Elements with Time Delays.
Scientific reports 6:21037 (2016)
Regulatory gene circuit motifs play crucial roles in performing and maintaining vital cellular functions. Frequently, theoretical studies of gene circuits focus on steady-state behaviors and do not include time delays. In this study, the inclusion of time delays is shown to entirely change the t...
Constructing a folding model for protein S6 guided by native fluctuations deduced from NMR structures.
Journal of Chemical Physics 143(24):243141 (2015)
The diversity in a set of protein nuclear magnetic resonance (NMR) structures provides an estimate of native state fluctuations that can be used to refine and enrich structure-based protein models (SBMs). Dynamics are an essential part of a protein's functional native state. The dynamics in the ...
Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision.
PNAS 112(29):E3836 (2015)
Angiogenesis is critical during development, wound repair, and cancer progression. During angiogenesis, some endothelial cells adopt a tip phenotype to lead the formation of new branching vessels; the trailing stalk cells proliferate to develop the vessel. Notch and VEGF signaling mediate the se...
Generalized Manning Condensation Model Captures the RNA Ion Atmosphere.
Physical Review Letters 114(25):258105 (2015)
RNA is highly sensitive to the ionic environment and typically requires Mg(2+) to form compact structures. There is a need for models capable of describing the ion atmosphere surrounding RNA with quantitative accuracy. We present a model of RNA electrostatics and apply it within coarse-grained m...
The Fe-S cluster-containing NEET proteins mitoNEET and NAF-1 as chemotherapeutic targets in breast cancer.
PNAS 112(12):3698 (2015)
Identification of novel drug targets and chemotherapeutic agents is a high priority in the fight against cancer. Here, we report that MAD-28, a designed cluvenone (CLV) derivative, binds to and destabilizes two members of a unique class of mitochondrial and endoplasmic reticulum (ER) 2Fe-2S prot...
Jagged-Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype.
PNAS 112(5):E402 (2015)
Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular D...
What protein folding teaches us about biological function and molecular machines.
Current Opinion in Structural Biology 30:57 (2015)
Protein folding was the first area of molecular biology for which a systematic statistical-mechanical analysis of dynamics was developed. As a result, folding is described as a process by which a disordered protein chain diffuses across a high-dimensional energy landscape and finally reaches the...
Cancer-Related NEET Proteins Transfer 2Fe-2S Clusters to Anamorsin, a Protein Required for Cytosolic Iron-Sulfur Cluster Biogenesis.
PLoS ONE 10(10):e0139699 (2015)
Iron-sulfur cluster biogenesis is executed by distinct protein assembly systems. Mammals have two systems, the mitochondrial Fe-S cluster assembly system (ISC) and the cytosolic assembly system (CIA), that are connected by an unknown mechanism. The human members of the NEET family of 2Fe-2S prot...
Dimeric interactions and complex formation using direct coevolutionary couplings.
Scientific reports 5:13652 (2015)
We develop a procedure to characterize the association of protein structures into homodimers using coevolutionary couplings extracted from Direct Coupling Analysis (DCA) in combination with Structure Based Models (SBM). Identification of dimerization contacts using DCA is more challenging than i...
Integrating molecular dynamics simulations with chemical probing experiments using SHAPE-FIT.
Methods in Enzymology 553:215 (2015)
Integration and calibration of molecular dynamics simulations with experimental data remain a challenging endeavor. We have developed a novel method to integrate chemical probing experiments with molecular simulations of RNA molecules by using a native structure-based model. Selective 2'-hydroxy...
Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis.
Frontiers in Oncology 5:155 (2015)
Transitions between epithelial and mesenchymal phenotypes - the epithelial to -mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) - are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also a...
Geometrical Frustration in Interleukin-33 Decouples the Dynamics of the Functional Element from the Folding Transition State Ensemble.
PLoS ONE 10(12):e0144067 (2015)
Interleukin-33 (IL-33) is currently the focus of multiple investigations into targeting pernicious inflammatory disorders. This mediator of inflammation plays a prevalent role in chronic disorders such as asthma, rheumatoid arthritis, and progressive heart disease. In order to better understand ...
Connecting thermal and mechanical protein (un)folding landscapes.
Biophysical Journal 107(12):2950 (2014)
Molecular dynamics simulations supplement single-molecule pulling experiments by providing the possibility of examining the full free energy landscape using many coordinates. Here, we use an all-atom structure-based model to study the force and temperature dependence of the unfolding of the prot...