Paul Robustelli
Assistant Professor of Chemistry
Neukom Cluster of Computational Science
Department of Biochemistry and Cell Biology
The Robustelli group develops and applies computational methods to obtain atomic-level descriptions of the functional motions of biomolecules, with a particular interest in intrinsically disordered proteins.
Contact
Department(s)
Chemistry
Education
- B.A. Pomona College 2002-2006
- Ph.D. University of Cambridge (with Michele Vendruscolo) 2006-2011
- NSF Postdoctoral Fellow, Columbia University (with Arthur G. Palmer III) 2011-2013
- Scientist, D.E. Shaw Research 2013-2019
Selected Publications
Zhu J, Salvatella X, Robustelli P. "Small Molecules Targeting the Disordered Transactivation Domain of the Androgen Receptor Induce the Formation of Collapsed Helical States." bioRxiv (preprint), (2021)
https://doi.org/10.1101/2021.12.23.474012
Robustell P, Ibanez-de-Opakua A, Campbell-Bezat C, Giordanetto F, Becker S, Zweckstette Mr, Pan AC, Shaw DE. "Molecular basis of small-molecule binding to α-synuclein", bioRxiv (preprint), (2021)
https://doi.org/10.1101/2021.01.22.426549
Robustelli P, Piana S, Shaw DE. "The mechanism of coupled folding-upon-binding of an intrinsically disordered protein" Journal of the American Chemical Society (2020)
https://doi.org/10.1021/jacs.0c03217
Piana S*, Robustelli P*, Tan D, Chen S, Shaw DE. "Development of a force field for the simulation of single-chain proteins and protein-protein complexes" Journal of Chemical Theory and Computation (2020)
https://doi.org/10.1021/acs.jctc.9b00251
Robustelli P, Piana S, Shaw DE "Developing a molecular dynamics force field for both folded and disordered protein states." Proceedings of the National Academy of Sciences (2018) 115(21):E4758-E4766
https://doi.org/10.1073/pnas.1800690115
Piana S, Donchev AG, Robustelli P, Shaw DE. Water dispersion interactions strongly influence simulated structural properties of disordered protein states. The Journal of Physical Chemistry B. (2015) 119(16):5113-23
https://doi.org/10.1021/jp508971m
Robustelli P, Stafford KA, Palmer III AG. Interpreting protein structural dynamics from NMR chemical shifts. Journal of the American Chemical Society. (2012), 134(14):6365-74
https://doi.org/10.1021/ja300265w
Neudecker P, Robustelli P, Cavalli A, Walsh P, Lundström P, Zarrine-Afsar A, Sharpe S, Vendruscolo M, Kay LE. "Structure of an intermediate state in protein folding and aggregation. Science. (2012) 336(6079):362-366
https://doi.org/10.1126/science.1214203
C Camilloni, P Robustelli, AD Simone, A Cavalli, M Vendruscolo "Characterization of the conformational equilibrium between the two major substates of RNase A using NMR chemical shifts" Journal of the American Chemical Society (2012) 134 (9), 3968-3971
https://doi.org/10.1021/ja210951z
Robustelli P, Kohlhoff K, Cavalli A, Vendruscolo M. Using NMR chemical shifts as structural restraints in molecular dynamics simulations of proteins. Structure. (2010) 18(8):923-33
Joining the Laboratory
The Robustelli laboratory is always eager to hear from prospective graduate students and postdoctoral scholars to discuss current opportunities to join us at Dartmouth.
We are broadly interested in using atomistic molecular simulations to model the conformational dynamics and molecular recognition mechanisms of intrinsically disordered proteins. We aim to use insights from simulations to understand, predict and ultimately design new dynamic and heterogeneous IDP binding interactions. Current focuses of the laboratory include understanding the molecular mechanisms and diving forces of small molecules binding to IDPs, dissecting the intermolecular interactions that drive IDP phase separation and aggregation, and rationally designing small molecule and biologic IDP binders that modulate these processes.
Graduate students can join the group through the Chemistry (https://chemistry.dartmouth.edu/graduate/phd-program) and Molecular & Cell Biology (https://graduate.dartmouth.edu/mcb/) PhD programs. Feel free to reach out to discuss potential projects and rotation opportunities.
At the postdoctoral level, we seek candidates with experience developing and applying advanced molecular simulation techniques which may include, but are not limited to, one or more of the following areas: enhanced sampling algorithms, maximum-entropy methods, adaptive sampling strategies, markov-state models, dimensionality reduction, clustering methods, protein or small molecule force field parameterization, alchemical free-energy calculations, de novo protein/biologics design, de novo small molecule drug design. Ideal candidates have a fascination with intrinsically disordered protein biophysics, experience integrating molecular simulations and biophysical experiments, feel comfortable in high-dimensional spaces, and are interested in rational drug design. Protein NMR experience (experimental or computational) is a plus.
The computational methods of our group are tightly integrated with biophysical experiments, particularly from NMR spectroscopy, and opportunities exist to collaborate with experimental groups and/or conduct biophysical experiments in-house. Our laboratory has access to excellent NMR facilities with high-throughput screening capabilities.
Based on the interdisciplinary nature of our research, there is substantial freedom to develop projects of mutual interest spanning a broad range of research areas related to IDP simulations, IDP molecular recognition, IDP NMR, and IDP drug design. Potential projects might include any combination of the following:
Enhanced Sampling Method Development
MD Analysis Methods (MSMs, Clustering, Dimensionality Reduction, Machine Learning)
Small Molecule/Biologic Inhibitor Design
Ensemble Based De Novo Design Algorithms
NMR Spectroscopy
Protein aggregation inhibition
Drugging biological condensates
Interested candidates should send an inquiry to Paul.J.Robustelli@Dartmouth.edu, including a CV, a brief description of your research experience, interests and aspirations, and a note about the potential project/area that you find most interesting. Examples of code you have written or a link to a GitHub page are encouraged.
About Dartmouth: Dartmouth College is private Ivy League Research University in Hanover, New Hampshire. The Dartmouth Department of Chemistry is a highly collaborative department which, in addition to traditional focus areas in biophysical chemistry, organic synthesis, materials chemistry, and inorganic chemistry, is currently establishing a growing community of computational chemistry scholars. Dartmouth Chemistry is part of a broader biomedical research community at Dartmouth made up of labs across the Dartmouth Geisel School of Medicine, Institute for Biomolecular Targeting, Molecular & Cellular Biology program and the Norris Cotton Cancer Center.
Hanover, New Hampshire is located along the Connecticut River on the border of New Hampshire and Vermont in the idyllic Upper Valley Region. The Upper Valley is known for its scenic mountains, lakes, and rivers and its network of charming small towns. The Upper Valley has a vibrant outdoor culture with extensive hiking, biking, and cross-country skiing trails, canoeing and kayaking, and proximity to a number of downhill skiing mountains. Hanover is located 2-hours from Boston, MA, 1.5 hours from Burlington, VT, 2.5 hours from Portland Maine, and 3 hours from Montreal, Quebec.