I am currently an Assistant Professor at UCSF working on computational structural biology and molecular biophysics. Previously I was a postdoctoral researcher UCSF at Prof. Andrej Šali laboratory and at University of Maryland at Prof. Garyk Papoian. I obtained a Ph.D. in Molecular Biophysics at Johns Hopkins University and a bachelors degree in Physics at Pontificia Universidad Católica de Chile.
My research is focused on building integrative, computational, and theoretical models to describe the structure and dynamics of proteins, nucleic acids, and carbohydrates to understand their function and evolution.
On my research I use theoretical and computational methods from molecular biophysics, statistical mechanics, stochastic modeling, molecular modeling, and scientific and statistical computing to understand how molecules work.
Ignacia obtained her PhD at Johns Hopkins University. At UCSF her research has focused on building integrative structure models of protein assemblies.
Neelesh obtained his PhD in Computational Biology from IISER Pune. His work includes building models of the NPC basket and its interacting proteins.
Kenneth received his PhD from Georgia State University. Kenneth will work developing multi-state models of viral proteins as potential anti-viral targets.
To fully map the structure-function relationships of protein assemblies it is essential to capture their compositional and conformational heterogeneities. To this end, we are currently developing a flexible and general scheme, implemented in the Integrative Modeling Platform (IMP), to represent, score, sample, and analyze models of multiple states and complexes. Particularly, we are developing methods based on solution or in vivo data capable of modeling the underlying structural diversity instead of modeling ensemble averages. The ability to perform structural studies using solution or in vivo data offers several advantages, including determining the structures of difficult-to-isolate protein assemblies in their native environments and describing their full range of structural dynamics. Our approach aims to increase the accuracy, precision, and completeness of the model and to provide an estimate of its uncertainty.More
Our research has demonstrated that one can harness genome-scale genetic mapping to enable the modeling of the structures of individual proteins or protein complexes. We have shown that genetic interactions measured using point-mutant epistatic miniarray profile (pE-MAP) or chemical genetics miniarray profiles (CG-MAP) approaches can be used to determine the structure of protein assemblies. Modeling of protein complexes based on genetic interaction data proved accurate, precise, and generalizable, suggesting that the approach can effectively obtain structural information from sparse genetic interaction datasets. However, disentangling direct and indirect relationships between residue positions and using these relationships to infer the roles of conformational heterogeneity and allostery remains challenging. We are currently developing methods to model heterogeneous and/or transient molecular assemblies based on genetic interaction data.More
The NPC mediates nucleocytoplasmic transport between the cytoplasm and nucleoplasm. In yeast, this large macromolecular assembly (~52 MDa) is composed of ~30 distinct Nups (~550 in total) arranged with C8 symmetry around the pore. Multiple NPC isoforms are present in cells, having different structures and compositions. We have applied our integrative modeling approach to determine the structures of these different states. We have focused on understanding how transitions between these states are accessed. Major structural modules of the NPC are held together by flexible connectors that provide strength and resilience in the manner of a suspension bridge. Notably, these connectors extend through the NPC inner-ring, interacting with all major nucleoporins. Our work is focused on obtaining high resolution structures of the different NPC states and describing the ensemble of possible conformation of connector Nups.More
We have established a pipeline for integrative structure determination of HIV-human protein complexes. This effort involves marrying cross-linking mass spectrometry (XL-MS), structural, biochemical, genetic, and proteomic data using an integrative modeling approach. We have applied this approach to determine the structure and structural dynamics of HIV-1 TAR (RNA) and Tat (protein) binding to the human super elongation complex to promote proviral transcription, and the solution structures of the A3G-Vif(HIV-1)-CRL5-CBFβ, Nef(HIV-1)-CD4[CD]–AP2Δμ2-CTD, and the mycobacterial polyketide synthase Pks13 protein complexes. However, structural characterization of host-pathogen protein assemblies remains challenging, largely due to their compositional and conformational heterogeneity. For instance, a high proportion of pathogen proteins contain intrinsically disordered regions. We continue to develop tools for incorporating orthogonal to build multi-state models of host-pathogen assemblies.More
Integrative (hybrid) structure determination casts the building of structural models as a computational optimization problem where knowledge about the assembly is encoded into the scoring function used to evaluate candidate models. Integrative modeling has a number of advantages; for example, an ensemble of models that fits all the data is generally more accurate and precise than that based on a subset of data, new types of data can be easily added, the accuracy and precision of the data as well models can be assessed, and preliminary models can guide the design of new experiments. Integrative structure determination maximizes the accuracy, precision, completeness, and efficiency of the structural models.More
A newly synthesized protein is just a string of amino acids. From there, the protein chain will start bending and folding into various forms, until, for many globular proteins, it will reach a unique three-dimensional shape, which will determine its specific function. Although this search is guided by a shallow gradient in the protein's energy landscape, this is still largely a trial and error process. From one trial to another, many concerted movements occur simultaneously in order to properly re-accommodate different parts of the protein. This process, which gives rise to internal friction, significantly slows down the initial phase of folding and determines overall how quickly the protein will make it to the final folded state.More
Phosphoinositide 3-kinases (PI3Ks), are a family of lipid kinases involved in a variety of cell functions such as cell growth, proliferation, motility, survival and intracellular trafficking. These enzymes act as key signal transducers in the cell. The gene PIK3CA has been found to be mutated in 12% of all tumor sequences deposited in the catalog of mutations in cancers. Several of these oncogenic mutations activate the enzyme by weakening the autoinhibitory interaction. We are using computational modeling to characterize the inter-domain interactions in the WT and mutants to elucidate the molecular mechanism by which oncogenic mutations lead to increased enzymatic activity.More
Li, Yen-Li, Caroline A. Langley, Caleigh M. Azumaya, Ignacia Echeverria, Nicholas M. Chesarino, Michael Emerman, Yifan Cheng, and John D. Gross. "The structural basis for HIV-1 Vif antagonism of human APOBEC3G." Nature (2023): 1-3. [LINK]
Kim, Sun Kyung, Miles Sasha Dickinson, Janet Finer-Moore, Ziqiang Guan, Robyn M. Kaake, Ignacia Echeverria, Jen Chen et al. "Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13." Nature Structural & Molecular Biology (2023): 1-13. [LINK]
Bouhaddou, Mehdi, Ann-Kathrin Reuschl, Benjamin J. Polacco, Lucy G. Thorne, Manisha R. Ummadi, Chengjin Ye, Romel Rosales et al. "SARS-CoV-2 Variants Evolve Convergent Strategies to Remodel the Host Response (preprint)." (2023). [LINK]
Echeverria, Ignacia, Hannes Braberg, Andrej Sali, and Nevan J. Krogan. Integrative structure determination of histones H3 and H4 using genetic interactions. FEBS J, (2022). [LINK] <
Braberg, Hannes, Ignacia Echeverria, Robyn M. Kaake, Andrej Sali, and Nevan J. Krogan. "From systems to structure—using genetic data to model protein structures." Nature Reviews Genetics (2022): 1-13.[LINK]
Akey, Christopher W.*, Digvijay Singh*, Christna Ouch*, Ignacia Echeverria*, Ilona Nudelman, Joseph M. Varberg, Zulin Yu et al. "Comprehensive structure and functional adaptations of the yeast nuclear pore complex." Cell (2022).[LINK]
Huang, Fang, Trang TT Nguyen, Ignacia Echeverria, Ramachandran Rakesh, Daniele C. Cary, Hana Paculova, Andrej Sali, Arthur Weiss, Boris Matija Peterlin, and Koh Fujinaga. "Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb." Elife 10 (2021): e68473.
Kaake, Robyn M.*, Ignacia Echeverria*, Seung Joong Kim, John Von Dollen, Nicholas M. Chesarino, Yuqing Feng, Clinton Yu et al. "Characterization of an A3G-VifHIV-1-CRL5-CBFβ Structure Using a Cross-linking Mass Spectrometry Pipeline for Integrative Modeling of Host–Pathogen Complexes." Molecular & Cellular Proteomics 20 (2021).
Saltzberg, Daniel J., Shruthi Viswanath, Ignacia Echeverria, Ilan E. Chemmama, Ben Webb, and Andrej Sali. "Using Integrative Modeling Platform to compute, validate, and archive a model of a protein complex structure." Protein Science 30, no. 1 (2021): 250-261.
Braberg, Hannes*, Ignacia Echeverria*, Stefan Bohn, Peter Cimermancic, Anthony Shiver, Richard Alexander, Jiewei Xu et al. "Genetic interaction mapping informs integrative structure determination of protein complexes." Science 370, no. 6522 (2020).
Kwon, Yonghwa, Robyn Kaake, Ignacia Echeverria, Marissa Suarez, Charlotte Stoneham, Peter W. Ramirez, Jacob Kress et al. "Structural Basis of CD4 Downregulation by HIV-1 Nef." bioRxiv (2020). [PDF]
Gutierrez, Craig, Ilan E. Chemmama, Haibin Mao, Clinton Yu, Ignacia Echeverria, Sarah A. Block, Scott D. Rychnovsky, Ning Zheng, Andrej Sali, and Lan Huang. "Structural dynamics of the human COP9 signalosome revealed by cross-linking mass spectrometry and integrative modeling." Proceedings of the National Academy of Sciences 117, no. 8 (2020): 4088-4098. [PDF]
Saltzberg, Daniel, Charles H. Greenberg, Shruthi Viswanath, Ilan Chemmama, Ben Webb, Riccardo Pellarin, Ignacia Echeverria, and Andrej Sali. "Modeling biological complexes using integrative modeling platform." In Biomolecular Simulations, pp. 353-377. Humana, New York, NY, 2019.
Kim, Seung Joong, Javier Fernandez-Martinez, Ilona Nudelman, Yi Shi, Wenzhu Zhang, Barak Raveh, Thurston Herricks, J.A. Hogan, Paula Upla. Ilan Chemmama, Riccardo Pellarin, Ignacia Echeverria, et al. "Integrative structure and functional anatomy of a nuclear pore complex." Microscopy and Microanalysis 24, no. S1 (2018): 1212-1213. [PDF]
Kim, Seung Joong, Javier Fernandez-Martinez, Ilona Nudelman, Yi Shi, Wenzhu Zhang, Barak Raveh, Thurston Herricks, J.A. Hogan, Paula Upla. Ilan Chemmama, Riccardo Pellarin, Ignacia Echeverria, et al. "Integrative structure and functional anatomy of a nuclear pore complex." Nature 555, no. 7697 (2018): 475. [PDF]
Zhuo, Coral Y.; Caitlin I. Stoddard; Jonathan B. Johnston; Michael J. Trnka; Ignacia Echeverria; Eugene Palovcak; Andrej Sali; Alma L. Burlingame; Yifan Cheng; Geeta J. Narlikar "Correspondence information about the; Geeta J. Narlikar "Regulation of Rvb1/Rvb2 by a Domain within the INO80 Chromatin Remodeling Complex Implicates the Yeast Rvbs as Protein Assembly Chaperones" Cell Reports (2017). [PDF]
Schulze-Gahmen, Ursula; Ignacia Echeverria,; Goran Stjepanovic; Yun Bai; Huasong Lu; Dina Schneidman-Duhovny; Jennifer Doudna; Qiang Zhou; Andrej Sali; James Hurley "Insights into HIV-1 proviral transcription from an integrative structure of the P- TEFb:AFF4:Tat:TAR complex" eLife Journal (2016). [PDF]
Ferrandino, Giuseppe; Juan Pablo Nicola; Yuly E. Sánchez; Echeverria, Ignacia; Yunlong Liu; L Mario Amzel; Nancy Carrasco "Na+ coordination at the Na2 site of the Na+/I− symporter" PNAS (2016). [PDF]
Echeverria, Ignacia; Yunlong Liu; Sandra B Gabelli; L Mario Amzel "PI3Kα oncogenic mutations weaken the interactions that stabilize the p110α/p85α heterodimer" FEBS Journal (2015). [PDF]
Winogradoff, David*; Echeverria, Ignacia*; Davit A Potoyan, and Garegin A. Papoian. "The acetylation landscape of the H4 histone tail: disentangling the interplay between the specific and cumulative effects." Journal of the American Chemical Society (2015). [PDF]
Echeverria, Ignacia and Garegin A. Papoian. "DNA Exit Ramps Are Revealed in the Binding Landscapes Obtained from Simulations in Helical Coordinates." PLoS Comput Biol 11(2): (2015). [LINK]
Echeverria, Ignacia and Garegin A. Papoian. "Perspectives on the coarse-graining models of DNA molecules" in Many-body effects and electrostatics in multi-scale computations of Biomolecules, Eds. Qiang Cui, Pengyu Ren and Markus Meuwly (Book chapter) [LINK]
Echeverria, Ignacia and Garegin A. Papoian. "Structural heterogeneity and dynamics of the unfolded ensemble" Isr. J. Chem. 53 (2014). [PDF]
Echeverria, Ignacia; Dmitrii E. Makarov; and Garegin A. Papoian. "Concerted dihedral rotations give rise to internal friction in unfolded proteins." Journal of the American Chemical Society 136,(2014): 8708–8713. [PDF] Highlighted in JACS select [LINK]
Echeverria, Ignacia, and L. Mario Amzel. "Estimation of Free-Energy Differences from Computed Work Distributions: An Application of Jarzynski’s Equality." The Journal of Physical Chemistry B 116.36 (2012): 10986-10995. [PDF]
Gabelli, Sandra B.; Echeverria, Ignacia et al. "Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects." Biophysical Reviews: 1-7. [LINK]
Echeverria, Ignacia, and L. Mario Amzel. "Disaccharide binding to galectin-1: free energy calculations and molecular recognition mechanism." Biophysical journal 100.9 (2011): 2283-2292. [PDF]
Echeverria, Ignacia, and L. Mario Amzel. "Helix propensities calculations for amino acids in alanine based peptides using Jarzynski's equality." Proteins: Structure, Function, and Bioinformatics 78.5 (2010): 1302-1310. [PDF]
Messing, Simon AJ, et al. "Structural insights into maize viviparous14, a key enzyme in the biosynthesis of the phytohormone abscisic acid." The Plant Cell 22.9 (2010): 2970-2980. [LINK]
Urquiza, Mauricio, et al. "α-Helix peptides designed from EBV-gH protein display higher antigenicity and induction of monocyte apoptosis than the native peptide." Amino acids 39.5 (2010): 1507-1519. [LINK]
"The QCRG (Quantitative Biosciences Institute Coronavirus Research Group) AViDD Program is an interdisciplinary program that aims to identify new direct-acting antivirals for SARS-CoV-2 and 19 other viruses."[LINK]
"HARC is a collaborative research center to study HIV Accessory and Regulatory Complexes."[LINK]
"The NCDIR center goal is develop technologies to reveal, analyze and interpret interactomes in numerous biological and hierarchical cellular contexts. "[LINK]
"IMP is an open-source, comprehensive, and extensible software that provides programmatic support for developing and distributing integrative structure modeling protocols"[LINK]