Toward an in silico Cell


for Members

Toward an in silico Cell

Friday, March 18, 2011

The New York Academy of Sciences

Accurately modeling the molecular behavior of a living cell remains a Holy Grail of the biomodeling community. Technological advances are allowing ever-higher resolution insights into the behavior of biomolecules in cell interiors, and are inspiring scores of laboratories to develop predictive models capable of explaining these insights. This symposium will attempt to capture the state-of-the-art in modeling of large biological systems by comparing modeling predictions with experimental findings. The Chemical Biology Discussion Group brings together chemists and biologists interested in learning about the latest ideas in rapidly developing fields. It provides a forum for lively discussion and for establishing collaborations between chemists armed with novel technologies and biologists receptive to using these approaches to solve their chosen biological problems.  

Reception to follow.

Presented by



*Presentation times are subject to change.

12:30 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Tom Leyh, PhD, Albert Einstein College of Medicine

12:40 PM

Molecular Simulations of Protein Diffusion & Thermodynamic Stability in the Bacterial Cytoplasm
Adrian Elcock, PhD, University of Iowa

1:25 PM

From Isolated Molecules to Intact Cells – Structure of Ribosomal Arrangements in vitro and in situ
Julio Ortiz, PhD, Max Planck Institute of Biochemistry, Germany

2:10 PM

Noise in an Inducible Genetic Switch: A Whole Cell Simulation Study
Zaida Luthey-Schulten, PhD, University of Illinois at Urbana-Champaign

3:00 PM

Coffee Break

3:30 PM

Dynamics of a Processive Brownian Machine: the Translating Ribosome
Ruben Gonzalez, PhD, Columbia University

4:15 PM

Viewing the Ribosome through the Computational Microscope
Klaus Schulten, PhD, University of Illinois at Urbana-Champaign

5:00 PM

Networking Reception


Tom S. Leyh, PhD

Albert Einstein College of Medicine

Professor Thomas S. Leyh, currently a member of the Department of Microbiology and Immunology at the Albert Einstein College of Medicine, received his PhD from the Biophysics Graduate Group the University of Pennsylvania, where his research focused on nuclear and electron-paramagnetic resonance studies of metal-ligand complexes at enzyme active sites. His training expanded to general studies of enzyme mechanism and catalysis in his postdoctoral work at The Institute for Cancer Research, PA. Broadly considered, Dr Leyh’s laboratory is engaged in a multidisciplinary pursuit of an understanding of the molecular basis of life at many levels. His group discovered the link between sulfur biology and GTPase function, substrate channeling in the sulfate activation pathway, the cysteine metabolome – a group of cysteine biosynthetic enzymes that coalesce to form an ‘energy pump’, and natural inhibitors of bacterial isoprenoid biosynthesis. The Leyh group is currently working on numerous problems including ancient and novel mechanisms of communication between the RNA and protein “worlds,” the molecular basis of selectivity in sulfotransferases, and antibiotic development. Dr Leyh reviews for various journals and has served as a scientific advisor at the NIH and the NSF.

Jennifer Henry, PhD

The New York Academy of Sciences


Adrian H. Elcock, PhD

University of Iowa

Adrian Elcock received his D.Phil. in physical chemistry from Oxford University, UK in 1994, having previously obtained a first-class honors degree in chemistry from the University of East Anglia, UK (1989). In 1995 he was awarded a Wellcome Trust International Prize Traveling Fellowship which took him to the research group of Professor J. Andrew McCammon at the University of California, San Diego. He remained in La Jolla until October 2000, when he joined the faculty of the Biochemistry department at the University of Iowa; he was awarded tenure and promoted to associate professor in summer 2006. Dr. Elcock’s work centers on developing and applying molecular simulation techniques to model a variety of biochemical systems. Active research projects range from simulations of small-molecule associations in water to simulations of large-scale molecular models of the bacterial cytoplasm.

Ruben L. Gonzalez, Jr., PhD

Columbia University

Ruben Gonzalez received a BS in Chemistry and Biochemistry from Florida International University (FIU) in 1995. While at FIU, he did undergraduate research with Prof. Stephen Winkle in the Department of Chemistry and Biochemistry, where he investigated the thermodynamics and kinetics of protein and carcinogen binding to unusual DNA structures. Gonzalez then moved to the Department of Chemistry at the University of California, Berkeley to do his doctoral research with Prof. Ignacio Tinoco. While in Prof. Tinoco's laboratory, Gonzalez's research interests focused on the structure and thermodynamics of a specific RNA structure, known as an RNA pseudoknot, which is involved in the translational control of gene expression in many viruses. In particular, Gonzalez was interested in how specific binding of divalent metal ions stabilize RNA pseudoknot structures. As part of his research in Prof. Tinoco's laboratory, Gonzalez helped develop now widely-used methodology for using cobalt (III) hexamine as a mimic of magnesium (II) hexahydrate in order to determine the solution structures of divalent metal ion binding sites in complex RNA structures using nuclear magnetic resonance spectroscopy. Upon obtaining his PhD in Chemistry in 2000, Dr Gonzalez moved to Stanford University where he did postdoctoral research as an American Cancer Society Postdoctoral Fellow in the laboratories of Prof. Joseph D. Puglisi in the Department of Structural Biology and Prof. Steven Chu in the Department of Physics and Applied Physics. While at Stanford, Dr Gonzalez helped integrate expertise from Profs Puglisi's and Chu's laboratories in order to pioneer the first single-molecule fluorescence investigations of the ribosome, the universally-conserved RNA-based molecular machine responsible for protein synthesis in all living cells. Dr Gonzalez joined the Department of Chemistry at Columbia University as an Assistant Professor in 2006. Research in his laboratory focuses on the biophysical chemistry and biochemistry of Nature's RNA-based molecular machines, with a current emphasis on the mechanism and regulation of protein synthesis by the ribosome. Research in Prof. Gonzalez's laboratory has been recognized with numerous awards, including a Burroughs Wellcome Fund Career Award in the Biomedical Sciences, a National Science Foundation CAREER Award, an American Cancer Society Research Scholar Award, a Columbia University RISE Award and, most recently, a Distinguished Columbia Faculty Award.

Zaida Luthey-Schulten, PhD

University of Illinois at Urbana-Champaign

Zaida (Zan) Luthey-Schulten received her PhD in Applied Mathematics and Chemistry from Harvard University. She went on to do post-doctoral research in biophysics at the Max-Planck Institute and the Department of Physics at the Technical University of Munich, developing together with K. Schulten and A. Szabo a first-passage time description of chemical reactions of polymer chains. Upon joining the faculty at the University of Illinois, Zan has worked on a number of fields ranging from the theory of protein folding, evolutionary and energetic analysis of protein/RNA complexes in translation, and most recently stochastic simulations of reactions in entire bacterial cells. Dr. Luthey-Schulten has served on numerous panels for the NSF, NIH, and DOE, and is a Fellow of the American Physical Society. As a co-PI of the NIH Resource for Macromolecular Modeling and Bioinformatics, she makes her programs publicly available through their popular visualization and analysis program, VMD. She is currently a William and Janet Lycan Professor of Chemistry with affiliate positions in the Department of Physics, Beckman Institute, and the Institute for Genomic Biology.

Julio Ortiz, PhD

Max Planck Institute of Biochemistry, Germany

Julio Ortiz began his career in electron microscopy in Venezuela, where he was born, with a helical
reconstruction of myosin thick filaments, under the supervision of Dr. Raúl Padrón at the Venezuelan Institute for Scientific Research (IVIC). After receiving a fellowship from the DAAD (Deutscher Akademischer Austausch Dienst), he moved to Germany where he received first hand training in cryoelectron microscopy from Dr. Kevin Leonard (EMBL, Heidelberg). Later, Ortiz’s doctoral thesis was focused on actomyosin complexes and supervised by Dr. Rasmus Schroeder in the Department of Dr. Ken Holmes (Max Plank Institute for Medical Research).

Turning his attention to tomography and associated techniques. Julio Ortiz went to the Max
Planck Institute of Biochemistry in Martinsried for his post-doctoral studies in the dept. of Dr.
Wolfgang Baumeister. He contributed to the development of an approach that proved one can
obtain meaningful structures by classifying and averaging particles or subtomograms essentially
moving single particle analysis from 2D to 3D. He presented the first ribosomal atlas of an intact
cell (S. melliferum). Ortiz and his supervised doctoral students, in collaboration with Dr. U. Hartl
(MPI of Biochemistry), addressed several problems related with spatial organization of ribosomes. They revealed the native 3D organization of polysomes and solved the structure of hibernating ribosomes in vitro and inside intact bacterial cells.

Klaus Schulten, PhD

University of Illinois at Urbana-Champaign

Klaus Schulten received his PhD in Chemical Physics from Harvard University. He then moved on to dohis post-doctoral research in biophysics at the Max-Planck Institute of Biophysical Chemistry in Göttingen, Germany, from where he moved on to his first faculty position at the Technical University Munich. In 1988 he joined the faculty of the University of Illinois in Urbana-Champaign (UIUC) where he is now serving as Swanlund Professor of Physics. He is also the Director of the National Institute of Health Resource of Macromolecular Modeling and Bioinformatics at the Beckman Institute at UIUC. Dr. Schulten develops and distributes innovative software tools that are used by thousands of researchers and students worldwide to explore biomolecular systems—VMD, a molecular dynamics graphics program; NAMD, scalable molecular dynamics for clusters and supercomputers; BioCoRE, a web-based collaborative biological research environment. In his research Dr. Schulten combines physics, chemistry, biology, computer science theory, and experiments as well as mathematics and software engineering; the group engages in many computational-experimental collaborations.


Molecular Simulations of Protein Diffusion & Thermodynamic Stability in the Bacterial Cytoplasm

Adrian H. Elcock, PhD, University of Iowa

Continuing developments in the field of structural biology mean that it is now possible to consider constructing atomically detailed models of intracellular environments. I will describe our lab’s efforts to construct, and perform dynamic simulations of, an initial model of the cytoplasm of Escherichia coli (see below). The model includes 50 different types of macromolecules in copy numbers reflecting their cytoplasmic concentrations, and comprises a simulation ‘cell’ of a width approximately one-tenth the diameter of a typical E. coli cell. The simulations offer a detailed view of molecular diffusion within the cytoplasm and suggest that, in order to quantitatively reproduce experimental estimates of the in vivo diffusion coefficient of GFP, account must be taken of non-specific, ‘sticky’ interactions between cytoplasmic components. Snapshots taken from the simulations also enable us to perform comparative calculations of the thermodynamic stabilities of model proteins in vivo and in vitro. Again, accurate reproduction of the available experimental estimates requires that we account for favourable interactions between the model proteins and the cytoplasmic environment: calculations that assume that only ‘macromolecular crowding effects’ operate produce qualitatively incorrect estimates of thermodynamic stability in vivo. The talk will conclude with a discussion of the (many) aspects of the model that require development if all biophysical aspects of intracellular environments are to be correctly modelled.

From Isolated Molecules to Intact Cells – Structure of Ribosomal Arrangements in vitro and in situ

Julio Ortiz, PhD, Max Planck Institute of Biochemistry, Germany

Cryoelectron tomography (CET) allows the visualization of flexible molecular structures both in vitro and in situ, i.e. in the functional environment of intact cells. To illustrate the opportunities provided by CET, two examples of spatial arrangements of ribosomes will be discussed in some detail, the native 3D organization of Escherichia coli ribosomes in polysomes and hibernating ribosomes (100S). We have applied CET to: a) E. coli lysates translating truncated mRNA to favor polysome formation; b) ribosome-enriched fractions of starved E. coli cells and c) intact E. coli cells grown in several conditions. We track the localization and orientation of ribosomes within tomograms using a known structure by template matching. Then, we align subtomograms containing single ribosomal particles to a common origin and average them to reveal details of the interaction between the identified complexes. We showed that E. coli ribosomes adopt two preferential relative orientations in densely-packed polysomes. These alternative manners of ribosomal pairing result in variable 3D polysomal organizations, i.e. pseudo-planar or pseudo-helical polysomes. It was also possible to purify in silico a particular ribosomal arrangement of the two 70S ribosomes that form a dimer in starvation conditions (100S ribosomes). Moreover, this 100S ribosomal arrangement has been detected in tomograms of intact E. coli cells only in stationary phase. We found distinctive spatial organization for translating and hibernating ribosomes. We hypothesize that polysomal organizations disfavor interaction between the non-folded nascent chains avoiding protein misfolding; whereas ribosome dimerization might protect the ribosomal subunits from degradation. In situ detection of the 100S ribosomes reinforces their physiological role as a storage form of ribosomes important for cell survival.

Noise in an Inducible Genetic Switch: A whole Cell Simulation Study

Zaida Luthey-Schulten, PhD, University of Illinois at Urbana-Champaign, Champaign, IL

Stochastic expression of genes can produce heterogeneity in clonal populations of bacteria under identical environmental conditions. We analyze and compare the behavior of the inducible lac genetic switch using well-stirred and spatially resolved simulations for Escherichia coli cells modeled under fast and slow-growth conditions. Our new kinetic model describing the switching of the lac operon from one phenotype to the other incorporates parameters obtained from recently published in vivo single-molecule fluorescence experiments along with in vitro rate constants. The simulations provide mRNA–protein probability landscapes, which demonstrate that switching is the result of crossing both mRNA and protein thresholds. Using cryoelectron tomography of an E. coli cell and data from proteomics studies, we construct spatial in vivo models of cells and quantify the noise contributions and effects on repressor rebinding due to cell
structure and crowding in the cytoplasm. The model for the fast-growth cells predicts a slight
decrease in the overall noise and an increase in the repressors rebinding rate due to anomalous
subdiffusion. Tomograms for E. coli grown under slow-growth conditions identify positions of
the ribosomes and the condensed nucleoid. The smaller slow-growth cells have increased mRNA
localization and a larger internal inducer concentration, leading to a significant decrease in the
lifetime of the repressor–operator complex and an increase in the frequency of transcriptional
bursts. The long time simulations of the cells under in vivo conditions of molecular crowding are
performed with a lattice-based reaction diffusion model that runs on graphics processing units

Dynamics of a Processive Brownian Machine: the Translating Ribosome

Ruben Gonzalez, Jr, PhD, Columbia University

Conformational rearrangements of the ribosome, its transfer RNA (tRNA) substrates, and its associated translation factors are hypothesized to play important mechanistic roles throughout all stages of protein synthesis. To determine how the structural dynamics of the translational machinery couple to the molecular mechanisms underlying protein synthesis, we are using single-molecule fluorescence resonance energy transfer (smFRET) to directly characterize these dynamics and their regulation during translation. In this lecture, we will describe the role that thermally activated structural fluctuations of the ribosome and its tRNA substrates play in enabling and regulating the mechanism of protein synthesis. Specifically, we will discuss how peptide bond formation during the addition of each amino acid to the nascent polypeptide chain enables the translating ribosome to undergo a large-scale, thermally activated structural rearrangement such that it transiently samples an obligatory intermediate that lies on the reaction pathway. We will present our on-going efforts to experimentally characterize the nature of the energetic barrier that governs this structural rearrangement, the role that ribosome and tRNA structure play in enabling thermal fluctuations to drive transitions over this barrier, and the mechanisms through which translation factors regulate this structural rearrangement as part of their mechanisms of action during protein synthesis. Collectively, our studies strongly suggest that protein synthesis is in large part driven and regulated by mechanisms that direct thermally activated, large-scale conformational fluctuations of the translational machinery.

Viewing the Ribosome through the Computational Microscope

Klaus Schulten, PhD, University of Illinois at Urbana-Champaign, Champaign, IL

The ribosome, a large macromolecular complex composed of over 50 proteins and RNA strands, altogether about 300,000 atoms, is responsible for translating the genetic information carried by mRNA into proteins, a process which occurs in multiple stages, each regulated through interactions with additional factors. Understanding how the ribosome connects the behavior of its smallest components to its large-scale functioning is a challenge being met by many different techniques, including molecular dynamics simulations. In this lecture, we describe how computational methodology has been utilized to address different aspects of translation by the ribosome. We illustrate first, how molecular dynamics, combining X-ray crystallographic and electron microscopy data, yields atomic resolution models of the ribosome in its various functional stages. We then report how nascent proteins in the ribosome can control genetic expression, e.g., stall the ribosome. We also show the first snapshot of a ribosome seen as it inserts a protein being synthesized into a cellular membrane. Lastly, we present various inner ribosome views during its so-called elongation cycle in which a new amino acid is added to a nascent protein in accordance with the mRNA message being read.


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