About

José N. Onuchic is the Harry C. and Olga K. Wiess Chair of Physics and a Professor of Chemistry and BioSciences at Rice University. His research has led the biological physics community to develop an integrated understanding of various biochemical and biological systems, spanning from molecular interactions to cellular and multi-cellular structures. His work has expanded into medical applications, particularly focusing on cancer. In the field of protein folding, he introduced the concept of protein folding funnels, which describe how convergent kinetic pathways guide folding to a unique, stable, native conformation. His theoretical framework, based on energy landscape theory and the funnel concept, addresses questions related to protein folding and function mechanisms. Additionally, he works on the theory of chemical reactions in condensed matter with an emphasis on biological electron transfer. His research interests also include stochastic effects in gene networks, with connections to bacterial decision-making and cancer, and his group is currently focusing on chromatin folding and function. Dr. Onuchic holds a BS in Electrical Engineering, a BS in Physics, and an MS in Applied Physics from Universidade de Sao Paulo, and a PhD in Chemistry from the California Institute of Technology.

Research topics

• Biology
• Computer Science
• Genetics
• Cell biology
• Computer Security
• Biochemistry
• Chemistry
• Biophysics
• Virology
• Computational biology
• Evolutionary biology
• Combinatorial chemistry
• Immunology
• Stereochemistry
• Medicine

Selected publications

• Exploring functional transitions of the 2’-dG riboswitch aptamer

  Proceedings of the National Academy of Sciences · 2026-04-13

  articleOpen accessSenior authorCorresponding

  Riboswitches are structural elements in the 5’ untranslated region of mRNAs that adopt different conformations under different conditions. Transitions between these different states are involved in controlling gene expression and occur on relatively slow timescales. The RNA structure based model is a coarse-grained description developed by combining structural information with electrostatic interactions for RNA molecules. The simplicity of this model allows for the exploration of longer timescales and the entire energy landscape of the riboswitch aptamer which is not possible with physical force fields. Molecular dynamics simulations using this simpler representation are consistent with explicit solvent simulations and SHAPE and NMR experiments. Our simulations reveal a temperature range, which includes room temperature, where the P1 helix is stable in the presence of ligand binding while flexible in the ligand-free state. These simulations suggest a multibasin free energy profile for the aptamer domain of the 2’-dG riboswitch, where the secondary structures are stably formed with a different organization of the tertiary structures, especially in the absence of the ligand. It is also suggested that the Mg 2+ ions have a significant stabilizing effect, especially on the tertiary structures and on the regulatory helix P1, creating magnesium-mediated attractive interactions between phosphate groups in some cases. The mechanism proposed by experimentalists for the functional transition requires the breaking of the P1 helix. This process occurs on relatively slow timescales, and therefore necessitates the proposed model which allows direct connection to experimental observations.

  PublisherDOI

• Exploring the energy landscape of bacterial chromosome segregation

  Proceedings of the National Academy of Sciences · 2026-03-17 · 1 citations

  articleOpen accessSenior authorCorresponding

  Faithful chromosome segregation during bacterial replication requires global reorganization of the nucleoid, where Structural Maintenance of Chromosomes (SMC) complexes play a crucial role. Here, we develop an energy landscape framework that integrates data-driven pairwise interactions with coarse-grained polymer physics to infer the 3D architectural ensembles of Escherichia coli and Bacillus subtilis chromosomes throughout replication. We show that SMC-mediated long-range lengthwise compaction reshapes the nucleoid to induce a robust mid-replication transition in which the terminus relocates toward the nucleoid center and duplicated origins segregate toward opposite cell halves. SMC-deficient mutants lack this transition and instead exhibit emergent nematic-like alignment of sister chromosomes that impedes segregation. A distinctive intersister Hi-C signature accompanies the emergence of the nematic alignment. By systematically tuning nonspecific intersister adhesion, we reveal that SMC activity expands the physical regime permitting faithful segregation. This buffering protects segregation against adhesive forces intrinsic to the crowded bacterial nucleoid. Our framework provides mechanistic insight into SMC-dependent coreplication segregation across bacterial species, yielding experimentally testable predictions for imaging and sister-chromosome-resolved Hi-C.

  PublisherDOI

• A biophysical framework for accurately identifying antigen single-amino acid escape variants and corresponding variant-specific compensatory TCR sequences

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-05

  articleOpen access

  ABSTRACT The impact of single amino acid substitution on T-cell receptor (TCR) recognition is central to understanding the molecular determinants of TCR specificity and degeneracy during viral mutational escape, cancer recognition, and autoimmunity. In this study, we developed a biophysics-informed computational approach integrating experimental alanine-scan mutagenesis data from the autoimmune-associated ALWGPDPAAA peptide bound to HLA-A*02:01 together with coarse-grained structural modeling. Our approach reconstructs the energetics and structural determinants underpinning the observed loss of recognition by the diabetogenic 1E6 TCR upon single-point mutations, specifically at the critical Pro 5 and Asp 6 residues. Leveraging the computational model’s ability to incorporate multiple structural templates into binding predictions, this approach quantitatively reproduces experimentally measured affinity disruptions. Additionally, we apply our approach to identify potential compensatory interactions capable of restoring binding affinity through alternative residue interactions. This integrative computational framework contributes a strategy for inferring TCR-peptide binding energetics at the single amino acid level, guiding the rational design of peptide-based immunotherapeutics, and predicting the functional impacts of clinically relevant peptide variants.

  PublisherOA PDFDOI

• A data-driven chromatin model reveals spatial and dynamic features of genome organization

  Proceedings of the National Academy of Sciences · 2026-01-23 · 1 citations

  articleOpen accessSenior author

  Compacting chromatin within the cellular nucleus presents a significant challenge for biology. Chromosomes must be both condensed and spatially organized to enable essential processes such as transcription and replication. Chromosome conformation capture experiments (e.g., Hi-C) provide valuable information about the spatial organization and, therefore, the connectivity between different genomic regions. These experiments inspired polymer models that describe the physical mechanism of the chromosomal energy landscape. The Full-Inversion Chromatin model (FI-Chrom), a data-driven approach for modeling genome organization, uses Hi-C contact maps to infer pairwise interaction potentials between all chromosomal loci. It combines Graphics Processing Unit (GPU)-accelerated simulations with efficient training of tens of millions of parameters derived from the maximum-entropy principle to determine 3D structures of chromosomes that accurately reproduce Hi-C-like data. FI-Chrom does not make any a priori assumptions regarding chromosome architecture, making it applicable to any chromosome conformation capture experiment. Its derived structural ensembles capture all essential features from the short- and long-range interactions of typical chromosome organization, such as segregated compartments, chromosome territories, and fully or partially formed loops. Although Hi-C contains only structural information, FI-Chrom extends these data by revealing an emergent dynamical mechanism encoded in the inferred energy landscape. For example, simulations show that chromatin loops are not static architectural features but rather transient structural elements. Statistical analyses further indicate that loops confined within a single compartment occur more frequently than those spanning multiple compartments, highlighting the dynamic and compartment-dependent nature of chromatin organization.

  PublisherOA PDFDOI

• Biguanides antithetically regulate tumor properties by the dose-dependent mitochondrial reprogramming-driven c-Src pathway

  Cell Reports Medicine · 2025-02-01 · 11 citations

  articleOpen access

  The biguanide metformin attenuates mitochondrial oxidation and is proposed as an anti-cancer therapy. However, recent clinical studies suggest increased proliferation and fatty acid β-oxidation (FAO) in a subgroup of patients with breast cancer (BC) after metformin therapy. Considering that FAO can activate Src kinase in aggressive triple-negative BC (TNBC), we postulate that low-dose biguanide-driven AMPK-ACC-FAO signaling may activate the Src pathway in TNBC. The low bioavailability of metformin in TNBC xenografts mimics metformin's in vitro low-dose effect. Pharmacological or genetic inhibition of FAO significantly enhances the anti-tumor properties of biguanides. Lower doses of biguanides induce and higher doses suppress Src signaling. Dasatinib and metformin synergistically inhibit TNBC patient-derived xenograft growth, but not in high-fat diet-fed mice. This combination also suppresses TNBC metastatic progression. A combination of biguanides with Src inhibitors provides synergy to target metastatic TNBC suffering with limited treatment options.

  PublisherOA PDFDOI

• Sequence-based calculation of local energetic frustration in proteins

  Structural Dynamics · 2025-11-01

  articleOpen access

  Given proteins' fundamental importance in human health and catalysis, the relationships between protein sequence, structure, dynamics, and function have become a topic of great interest. One way to extract information from proteins is to compute the local energetic frustration of their native state. Traditionally, energetic frustration calculations require protein structures as a starting point. However, using a single protein structure to evaluate the energetic frustration for a given amino acid sequence does not always fully represent the protein's structural ensemble. Therefore, we have developed a sequence-based method to evaluate energetic frustration in proteins using direct coupling analysis and statistical potentials. Our approach exhibits significant agreement with established structure-based frustration methods in terms of their mutual agreement with crystallographic B-factor. Moreover, our sequence-based method shows elevated precision in classifying high B-factor residues, suggesting that it has some robustness to unstructured regions of proteins.

  PublisherOA PDFDOI

• Quantum simulation of charge and exciton transfer in multi-mode models using engineered reservoirs

  Nature Communications · 2025-12-05

  articleOpen access

  Quantum simulation enables studies of open-system dynamics in non-perturbative regimes by programming electronic, vibrational, and environmental interactions on comparable energy scales. Trapped ions offer this capability, combining spins, phonons, and tunable dissipation on one platform. We demonstrate an open-system quantum simulation of charge and exciton transfer in a multi-mode linear vibronic coupling model. Using tailored spin-phonon interactions with reservoir engineering, we emulate a system with two dissipative vibrational modes coupled to donor and acceptor sites and track its non-equilibrium dynamics. We continuously tune the system from the charge transfer regime to the vibrationally assisted exciton transfer regime and find that degenerate modes enhance transfer rates at large energy gaps, while non-degenerate modes activate pathways that reduce the energy-gap dependence. Thus, the presence of one additional vibration introduces interfering pathways and reshapes non-perturbative excitation transfer. Our results establish a scalable, hardware-efficient route to simulate vibronic processes with engineered environments. Recent developments in trapped-ion platforms are opening towards quantum simulation of chemical dynamics. Here, the authors demonstrate independent control of spin-phonon coupling and reservoir engineering in a two-mode trapped-ion system to simulate excitation transfer dynamics.

  PublisherOA PDFDOI

• Critical Role of Mg²⁺ Ions in RNA Folding Transitions: Anchoring the A-Minor Twist in the SAM-II Riboswitch

  The Journal of Physical Chemistry B · 2025-09-02 · 4 citations

  articleOpen access

  Magnesium ions (Mg2+) play a crucial role in stabilizing various RNA tertiary motifs, such as pseudoknots, G-quadruplexes, kissing loops, and A-minor motifs, to name a few. Despite their importance, the precise location and role of Mg2+ ions in RNA folding are challenging to characterize both experimentally and computationally. In this study, we employ an all-atom structure-based model integrated with the dynamic counterion condensation (DCC) model to investigate the folding and unfolding transitions of apo SAM-II riboswitch RNA at physiological concentrations of Mg2+. Using the Energy Landscape Visualization Method (ELViM), we trace the transitions between conformational phases, focusing on magnesium interactions. ELViM reveals key structural ensembles during the transition from the unfolded to the folded state, facilitated by a partially folded intermediate, which is conformationally similar to that found in early 13C-CEST NMR. Interestingly, this study finds the rate-limiting transition from the unfolded state to this intermediate initiated by the formation of an A-minor twist interaction, a stable scaffold in the aptamer domain, stabilized by specific Mg2+ coordination. The contact probability map shows that this specific Mg2+ bridges a helical region and an internal loop, mitigating electrostatic repulsion at the phosphate level. As a result, a set of hydrogen-bond-mediated interactions between the loop and the minor groove of the helix is stabilized, supporting the formation of the A-minor twist. This study underscores the critical role of Mg2+ in driving the rate-limiting event of RNA folding and highlights its strategic location in stabilizing the A-minor twist motif, essential for the global packing and regulatory function of the SAM-II riboswitch aptamer.

  PublisherOA PDFDOI

• BPS2025 - Structure and inhibition of SARS-CoV-2 spike refolding in membranes

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• Conformational ligand-directed targeting of calcium-dependent receptors in acute trauma

  Med · 2025-07-01 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• The energy landscape for folding and function of biomolecules: integrating physical models, genetic information and experiments

  NSF · $1.4M · 2016–2023

• Collaborative Research: International Physics of Living Systems Graduate Research Network

  NSF · $3.4M · 2021–2026

• Collaborative Research: PoLS Student Research Network

  NSF · $3.0M · 2015–2022

• Understanding Protein Folding: Quantitative Connections Between Energy Landscape Theory and Experiments

  NSF · $750k · 2001–2006

• Center for Theoretical Biological Physics

  NSF · $11.1M · 2008–2013

Frequent coauthors

• Herbert Levine

  Northeastern University

  313 shared

• Vinícius G. Contessoto

  169 shared

• Peter G. Wolynes

  Rice University

  162 shared

• Mohit Kumar Jolly

  Indian Institute of Science Bangalore

  157 shared

• Eshel Ben‐Jacob

  132 shared

• Federico Bocci

  University of California, Irvine

  131 shared

• Dongya Jia

  123 shared

• Mingyang Lu

  Nanchang University

  120 shared