Advances in Protein Science Powered by Massively Parallel Molecular Dynamics Software
Medical, Health Informatics and Computational Biology Accomplishment | 2015
Where the work was done: IBM T.J. Watson Research Center, IBM Research Almaden and IBM Research Zurick
What we accomplished: Over the past years, we have illuminated fundamental principles governing a myriad of biological processes in protein folding/misfolding/aggregation and at the bio-nano interface by combining experimental and theoretical approaches. In a paradigm-shifting fashion, we have:
(1) Demonstrated the potential for nanoscale dewetting during protein folding.
(2) Revealed how a single mutation induces protein misfolding and aggregation in proteins related to Alzheimer's disease.
(3) Resolved the mechanism underlying UV radiation-induced gamma-crystallin polymerization implicated in cataract formation.
(4) Illustrated the potential effects of nanoparticles on biomolecules in the sphere of nanotoxicity plus nanomedicine.
(5) Performed the largest set of mutations ever configured for free energy perturbation calculation to identify potential tastants for IBM clients.
Our state-of-the-art simulations based on massively parallel molecular dynamics software helped alter the landscape of the molecular modeling field, transforming molecular dynamics from a largely theoretical toy into a technique well-suited for direct comparison with experiments. These works have resulted in over 20 patents, 2 books and over 100 publications in peer reviewed journals including high impacts ones such as Nature, Science, Cell, PNAS, PLoS Medicine, JACS, ACS Nano and Angewandte Chemie.
In addition, techniques and tools developed for these projects have helped to land funded projects from some top Fortune 500 companies to conduct research related to their core businesses.
- Science 2004: Hydrophobic Collapse in Multi-domain Protein Folding, [cited 355]
- Nature 2005: Observation of a Dewetting Transition in the Collapse of the Melittin Tetramer, [cited 256]
- Cell 2006: A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes, [cited 1058]
- Nature Nanotech. 2013: Destructive Extraction of Phospholipids from E. Coli Membrane by a Graphene Nanosheet, [cited 121]
- Nature Medicine 2012: Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia, [cited 153]
- Nature Commun. 2013: Supramolecular high-aspect ratio assemblies with strong antifungal activity
- Nature Commun. 2012: Comprehensive Interrogation of Natural TALE DNA Binding Modules and Transcriptional Repressor Domains, [cited 155]
- Proc. Natl. Acad. Sci. 2015: Even with non-native interactions, the updated folding transition states of the homologs Protein G & L are extensive and similar
- Proc. Natl. Acad. Sci. 2014: How Force Unfolding Differs from Chemical Denaturation
- Proc. Natl. Acad. Sci. 2013: Salts Drive Controllable Multi-Layered Upright Assembly of Amyloid-like Peptides at Mica/Water Interface
- Proc. Natl. Acad. Sci. 2012 (featured article): Molecular Mechanism of Pancreatic Tumor Metastases Inhibition by Metallofullerenol Gd@C82(OH)22: Implication for de novo Design of Nanomedicine, [cited 71]
- Proc. Natl. Acad. Sci. 2011 (featured article): Aggregation of Partially Folded gamma-Crystallin Associated with Human Cataracts via Domain Swapping at the C-terminal beta-strands
- Proc. Natl. Acad. Sci. 2011 (featured article): Binding of human serum proteins on single-wall carbon nanotubes reduces cytotoxicity, [cited 312]
- Proc. Natl. Acad. Sci. 2009: Water-mediated signal multiplication with Y-shaped carbon nanotubes, [cited 72]
- Proc. Natl. Acad. Sci. 2008: Urea denaturation by stronger dispersion interactions with proteins than water implies a 2-stage unfolding, [cited 227]
- Proc. Natl. Acad. Sci. 2007: Electrostatic Gating of a Nanometer Water Channel, [cited 197]
- Proc. Natl. Acad. Sci. 2007: Destruction of long-range interactions by a single mutation in lysozyme, [cited 64]
- Proc. Natl. Acad. Sci. 2006: A role for direct interactions in the modulation of rhodopsin by omega-3 polyunsaturated lipids [cited 177]
- Proc. Natl. Acad. Sci. 2006: Short blocks from the noncoding parts of the human genome have instances within nearly all known genes and relate to biological processes, [cited 107]
- Annu. Rev. Phys. Chem. 2009: Dewetting and Hydrophobic Interaction in Physical and Biological Systems, [cited 218]
- J. Am. Chem. Soc. 2015: A peptide-coated gold nanocluster exhibits unique behavior in protein activity inhibition
- J. Am. Chem. Soc. 2013: Hydrophobic Interaction Drives Surface-Assisted Epitaxial Assembly of Amyloid-like Peptides
- J. Am. Chem. Soc. 2013: Interplay between Drying and Stability of a TIM Barrel Protein: A Combined Simulation-Experimental Study
- J. Am. Chem. Soc. 2012: Collapse of Unfolded Proteins in a Mixture of Denaturants
- J. Am. Chem. Soc. 2009: Urea's Action on Hydrophobic Interactions, [cited 134]
- J. Am. Chem. Soc. 2008: Role of Water in Mediating the Assembly of Alzheimer Amyloid-beta Abeta16-22 Protofilaments, [cited 106]
- J. Am. Chem. Soc. 2008: Metal− Carbon Nanotube Contacts: The Link between Schottky Barrier and Chemical Bonding
- J. Am. Chem. Soc. 2006: Retinal counterion switch mechanism in vision evaluated by molecular simulations, [cited 68]
- J. Am. Chem. Soc. 2006: Thermal denaturing of mutant lysozyme with both OPLSAA and CHARMM force fields, [cited 51]
- J. Am. Chem. Soc. 2006: Hydration and Dewetting near Fluoronated Superhydrophobic Plates
- J. Am. Chem. Soc. 2005: Role of Cholesterol and Polyunsaturated Chains in Lipid−Protein Interactions: Molecular Dynamics Simulation of Rhodopsin in a Realistic Membrane Environment, [cited 88]
- Angew. Chem. Intl. Ed. 2014: Irreversible Denaturation of Proteins due to Aluminum-induced Formation of Ring Structures
- Genome research 2010: Dynamic changes in the human methylome during differentiation, [cited 519]
- Nano Lett. 2014: Image Distortions of a Partially Fluorinated Hydrocarbon Molecule in Atomic Force Microscopy with Carbon Monoxide Terminated Tips
- ACS Nano 2015: Reduced Cytotoxicity of Graphene Nanosheets Mediated by Blood-Protein Coating
- ACS Nano 2015: Potential Toxicity of Graphene to Cell Functions via Disrupting Protein-Protein Interactions
- ACS Nano 2015: Gd-Metallofullerenol Nanomaterial Suppresses Pancreatic Cancer Metastasis by Inhibiting the Interaction of Histone Deacetylase 1 and Metastasis-Associated Protein 1
- ACS Nano 2013: Pattern Placement Accuracy in Block Copolymer Directed Self-Assembly Based on Chemical Epitaxy
- ACS Nano 2012: Molecular Mechanism of Surface-Assisted Epitaxial Self-Assembly of Amyloid-like Peptides
- ACS Nano 2012: Probing the self-assembly pathway of diphenylalanine-based nanovesicles and nanotubes, [cited 50]
- ACS Nano 2010: Plugging Into Proteins: Poisoning Protein Function by a Hydrophobic Nanoparticle, [cited 87]
- Briefings in Bioinformatics 2012: Multiscale modeling of macromolecular biosystems
Image credit: IBM Research