We are investigating the molecular origin of internal friction in unfolded proteins.
Using a helical coordinate system we are charaterizing the enviroments surrounding DNA molecules.
We are developing and implemeting methods to compute free energy differences from non-equilibrium simulations.
We are studying how oncogenic mutations affect the activation mechanism of PI3Kα.
I am currently an Assistant Professor at UCSF working on integrative modeling and host-pathogen interactions. 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.
The overall goal of my research is to obtain rigorous mechanistic insight into the structure and dynamics of macromolecular complexes, with special emphasis on how the interaction between proteins, DNA and carbohydrates determine their biologically relevant function.
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.
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
Protein-DNA and ion-DNA interactions are key for many essential biological activities. DNA-binding proteins have to bind tightly to their specific targets, while also being able to find the specific site in an efficient way. To facilitate the search of their specific DNA targets, DNA binding proteins often associate non-specifically to DNA and then slide along the DNA. Using computational modeling we quantitatively described the energetics of sliding and binding of two small ligands to the DNA's minor groove and show that the free-energy landscape surrounding DNA molecules provides heterogeneous binding environments. Such differences in the free-energy landscape can be exploited by DNA-binding proteins.More
There is considerable interest in developing molecular models capable of identifying the molecular mechanism that hinders DNA organization and dynamics. These processes involve DNA segments of varying length ranging from tens to up to thousands of nucleotides. The large scale and its complexity have proven to set a challenge over the type of phenomena that can be investigated computationally. Even though fully atomistic MD simulations for small systems are feasible, these models might not be practical or even desirable to investigate the mesoscopic properties of DNA complexes. We are currently developing accurate novel computational techniques that are capable of covering the required length and timescales.More comming soon
Equilibrium free-energy differences can be computed from nonequilibrium molecular dynamics (MD) simulations using Jarzynski’s equality (PRL 1997) by combining a large set of independent trajectories (path ensemble). We developed the multistep trajectory combination (MSTC) method to compute free-energy differences, which by combining trajectories carried out in steps, significantly reduces the number of trajectories necessary to generate a representative path ensemble. This method generates well-sampled work distributions, even for large systems. The MSTC method significantly reduces both the bias and variance of the free-energy estimates compared to the estimates obtained using single-step trajectories.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
Galectin-1, a carbohydrate-binding protein with affinity for β-galactosides, is a key modulator of diverse cell functions such as immune response. We studied the binding affinity and specificity of galectin-1 for different β-galactosides and determined that the small differences in affinity among the disaccharides are the result of an exquisite balance between the strengths of the galectin-sugar HBs and the HBs the protein and the disaccharides make with the solvent. The free energies along the reaction coordinate shows that disaccharide unbinding/binding presents no energetic barrier and, therefore, is diffusion-limited. We also determined that breaking of the protein-disaccharide HBs takes place in stages with intermediate states in which the interactions are bridged by water molecules.More
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]
"Computational structural biology and bioinformatic group at the Department of Bioengineering and Therapeutic Sciences at the University of California, San Francisco"[LINK]
"Open source C++ and Python toolbox for solving complex modeling problems by integrating data from diverse biochemical and biophysical experiments"[LINK]
"Theoretical physical chemistry group in the Department of Chemistry and Biochemistry at the University of Maryland where I was a postdoc"[LINK]
"Structural Enzymology and Thermodynamics group in the Department of Biophysics and Biophysical Chemistry at Johns Hopkins University School of Medicine"[LINK]