Honors & Awards

  • Genentech Fellowship, Columbia University (2011)
  • EXROP Fellowship, Howard Hughes Medical Institute (2012)
  • ADVANCE Fellowship, Stanford ADVANCE (2013)
  • NSF Graduate Research Fellowship, National Science Foundation (2013)

Education & Certifications

  • BSc, Columbia University, Applied Mathematics (2013)


All Publications

  • Markov State Models Provide Insights into Dynamic Modulation of Protein Function ACCOUNTS OF CHEMICAL RESEARCH Shukla, D., Hernandez, C. X., Weber, J. K., Pande, V. S. 2015; 48 (2): 414-422


    CONSPECTUS: Protein function is inextricably linked to protein dynamics. As we move from a static structural picture to a dynamic ensemble view of protein structure and function, novel computational paradigms are required for observing and understanding conformational dynamics of proteins and its functional implications. In principle, molecular dynamics simulations can provide the time evolution of atomistic models of proteins, but the long time scales associated with functional dynamics make it difficult to observe rare dynamical transitions. The issue of extracting essential functional components of protein dynamics from noisy simulation data presents another set of challenges in obtaining an unbiased understanding of protein motions. Therefore, a methodology that provides a statistical framework for efficient sampling and a human-readable view of the key aspects of functional dynamics from data analysis is required. The Markov state model (MSM), which has recently become popular worldwide for studying protein dynamics, is an example of such a framework. In this Account, we review the use of Markov state models for efficient sampling of the hierarchy of time scales associated with protein dynamics, automatic identification of key conformational states, and the degrees of freedom associated with slow dynamical processes. Applications of MSMs for studying long time scale phenomena such as activation mechanisms of cellular signaling proteins has yielded novel insights into protein function. In particular, from MSMs built using large-scale simulations of GPCRs and kinases, we have shown that complex conformational changes in proteins can be described in terms of structural changes in key structural motifs or "molecular switches" within the protein, the transitions between functionally active and inactive states of proteins proceed via multiple pathways, and ligand or substrate binding modulates the flux through these pathways. Finally, MSMs also provide a theoretical toolbox for studying the effect of nonequilibrium perturbations on conformational dynamics. Considering that protein dynamics in vivo occur under nonequilibrium conditions, MSMs coupled with nonequilibrium statistical mechanics provide a way to connect cellular components to their functional environments. Nonequilibrium perturbations of protein folding MSMs reveal the presence of dynamically frozen glass-like states in their conformational landscape. These frozen states are also observed to be rich in β-sheets, which indicates their possible role in the nucleation of β-sheet rich aggregates such as those observed in amyloid-fibril formation. Finally, we describe how MSMs have been used to understand the dynamical behavior of intrinsically disordered proteins such as amyloid-β, human islet amyloid polypeptide, and p53. While certainly not a panacea for studying functional dynamics, MSMs provide a rigorous theoretical foundation for understanding complex entropically dominated processes and a convenient lens for viewing protein motions.

    View details for DOI 10.1021/ar5002999

    View details for Web of Science ID 000349806300028

    View details for PubMedID 25625937

  • MDTraj: a modern, open library for the analysis of molecular dynamics trajectories bioRxiv McGibbon, R. T., Beauchamp, K. A., Schwantes, C. R., Wang, L., Hernandez, C. X., Harrigan, M. P., Lane, T. J., Swails, J. M., Pande, V. S. 2014

    View details for DOI 10.1101/008896

  • Structure-based network analysis of an evolved G protein-coupled receptor homodimer interface PROTEIN SCIENCE Nichols, S. E., Hernandez, C. X., Wang, Y., McCammon, J. A. 2013; 22 (6): 745-754


    Crystallographic structures and experimental assays of human CXC chemokine receptor type 4 (CXCR4) provide strong evidence for the capacity to homodimerize, potentially as a means of allosteric regulation. Even so, how this homodimer forms and its biological significance has yet to be fully characterized. By applying principles from network analysis, sequence-based approaches such as statistical coupling analysis to determine coevolutionary residues, can be used in conjunction with molecular dynamics simulations to identify residues relevant to dimerization. Here, the predominant coevolution sector lies along the observed dimer interface, suggesting functional relevance. Furthermore, coevolution scoring provides a basis for determining significant nodes, termed hubs, in the network formed by residues found along the interface of the homodimer. These node residues coincide with hotspots indicating potential druggability. Drug design efforts targeting such key residues could potentially result in modulation of binding and therapeutic benefits for disease states, such as lung cancers, lymphomas and latent HIV-1 infection. Furthermore, this method may be applied to any protein-protein interaction.

    View details for DOI 10.1002/pro.2258

    View details for Web of Science ID 000319422500007

    View details for PubMedID 23553730

  • Understanding the Origins of a Pandemic Virus arXiv Hernández, C. X., Chan, J., Khiabanian, H., Rabadan, R. 2011
  • The Origin and Evolution of a Pandemic Virus MAGNet/C2B2 Annual Retreat Carpenter, Z. W., Hernández, C. X., Chan, J., Rabadan, R. 2011

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