02 JUNE 2021 | 11AM (EDT) / 5PM (CEST)
Machine learning and statistical inference techniques to describe intrinsically disordered protein ensembles
We present our recent work in building ML/AI approaches to describe conformational transitions within intrinsically disordered protein ensembles (IDPs). IDPs challenge the traditional protein structure–function paradigm by adapting their conformations in response to specific binding partners leading them to mediate diverse, and often complex cellular functions such as biological signaling, self-organization and compartmentalization. Obtaining mechanistic insights into their function can therefore be challenging for traditional structural determination techniques. Often, scientists have to rely on piecemeal evidence drawn from diverse experimental techniques to characterize their functional mechanisms. Multi-scale simulations can help bridge critical knowledge gaps about IDP structure-function relationships — however, these techniques also face challenges in resolving emergent phenomena within IDP conformational ensembles. We posit that ML/AI techniques can effectively integrate information gleaned from multiple experimental techniques as well as from simulations in obtaining quantitative insights into complex/ emergent phenomena within these biological systems. We highlight three different aspects of ML/AI approaches: (1) in building biophysically meaningful collective variables that describe conformational transitions in IDP ensembles; (2) using AI-driven approaches to sample rare conformational fluctuations in IDP conformational landscapes; and (3) integrating small angle scattering and nuclear magnetic resonance experiments to probe conformational states accessed and to refine force-field parameters based on their collective descriptions. Together, our approaches highlight how ML/AI could be an integrated aspect for probing IDP-mediated biological phenomena.
Arvind Ramanathan is a computational biologist in the Data Science and Learning Division at Argonne National Laboratory and a senior scientist at the University of Chicago Consortium for Advanced Science and Engineering (CASE). His research interests are at the intersection of data science, high performance computing and biological/biomedical sciences. His research focuses on developing principled and scalable statistical inference techniques for analysis and development of adaptive multi-scale molecular simulations for studying complex biological phenomena (such as how intrinsically disordered proteins self assemble, or how small molecules modulate disordered protein ensembles). He obtained his Ph.D. in computational biology from Carnegie Mellon University, and was the team lead for integrative systems biology team within the Computational Science, Engineering and Division at Oak Ridge National Laboratory. More information about his group and research interests can be found at here.
07 JULY 2021 | 11AM (EDT) / 5PM (CEST)
From a Design on a Napkin to a Clinical Trial: a 20-year quest to improve survival for Ewing sarcoma patients
In 2009, Dr. Toretsky and his team revealed the molecule called YK-4-279 that targets Ewing sarcoma with an article in Nature Medicine. A deeper investigation into the mechanism of YK-4-279 has led Dr. Toretsky into the world of phase separation and soft matter. An analog of YK-4-279 called TK216 is in human clinical trials and seems to be helping some patients. This is the story that will be told.
Dr. Jeffrey Toretsky received his MD in 1988 from the University of Minnesota. He completed his pediatric residency at the Medical College of Virginia in 1991, and his pediatric oncology fellowship at the National Cancer Institute Pediatric Branch in 1997. In 2002, Dr. Toretsky was recruited from the University of Maryland to Georgetown University; where he was promoted to full professor with tenure in 2011. He was inducted into the American Society of Clinical Investigation in 2007 and received the Burroughs-Wellcome Clinical Scientist Award in Translational Research in 2008. In 2018, Toretsky was inducted into the National Academy of Inventors.
Dr. Toretsky actively pursues research that will lead to new and more specific therapies for a very rare cancer, Ewing sarcoma. His work focuses on Ewing sarcoma, since the tumors contain a unique target that is not found in non-tumor cells. This unique target offers an opportunity to create new medicines that will more specifically eliminate tumor growth while sparing normal cells. In 2009, Dr. Toretsky and his team revealed the molecule called YK-4-279 that targets Ewing sarcoma with an article in Nature Medicine. YK-4-279 has the potential to be a potent new strategy in the fight against not only Ewing sarcoma, but also other cancers and diseases with similar characteristics. A deeper investigation into the mechanism of YK-4-279 has led Dr. Toretsky into the world of phase separation and soft matter. He is particularly interested in understanding how protein complexes he called ‘assemblages’ occur and how they function in RNA processing. Along with this, he cofounded Tokalas, Inc., now Oncternal, Inc., to advance YK-4-279 to a clinical trial that began in the spring of 2016.
Dr. Toretsky is now Chief of the Division of Pediatric Adolescent and Young Adult Hematology/Oncology at Georgetown University. He continues to be the principal investigator of his NIH-funded laboratory group, leads the Molecular Oncology Program of the Lombardi Comprehensive Cancer Center, and co-leads a multidisciplinary sarcoma clinic at Children’s National Medical Center. He continues to be engaged in teaching at levels from high school through faculty mentoring. His wife, three children, dogs (Lucy and Greta), a passion for SCUBA diving and a clarinet support him in these endeavors.
01 SEPT 2021 | 11AM (EDT) / 5PM (CEST)
Drugging Important Cancer Targets Like KRAS
Numerous highly validated drug targets in oncology remain undrugged despite many of them being discovery 40 years ago. Boehringer Ingelheim is targeting many of these proteins in its drug discovery efforts – with KRAS being a target of particular focus. KRAS drives 1 in 7 of all human cancers and 90% of the KRAS driven cancers are caused by 9 different KRAS mutants. It took 39 years for the first drug approval against the first KRAS mutant KRASG12C after Channing Der’s discovery in 1982 that KRAS is an oncogene. But KRASG12C is but one of the 9 major cancer causing KRAS mutants and resistance, both intrinsic and acquired, appears to limit response rates and duration of response. This talk will provide an overview of the field and highlight the current and future challenges that need to be overcome. The talk will also highlight the multiple pan-KRAS and selective KRAS concepts that Boehringer-Ingelheim is pursuing to drug all forms of KRAS. The specific programs that will be presented include pan-KRAS inhibitors and pan-KRAS PROTACs (Proteolysis Targeting Chimeras), selective KRASG12C and KRASG12D inhibitors and SOS1 inhibitors. Historical screening efforts, particularly in the protein-protein interaction field, including successes and pitfalls will be also mentioned.
Darryl McConnell is currently Senior Vice President and Research Site Head at Boehringer-Ingelheim Regional Centre Vienna, Austria. His goal is to discover new chemical therapeutics for cancer’s Big 4 and beyond with the team at BI. Darryl’s interests lie in drugging protein-protein interactions, kinases and pushing the frontiers of PROTACs for cancer patients. Fragment screening, protein crystallography, protein NMR, drug resistance and natural product inspired medicinal chemistry are some of his areas of scientific interest.
Darryl commenced his career with Boehringer-Ingelheim in 2002 as a Research Laboratory Head and has been in his current role since 2015. Prior to this Darryl has worked for Intervet in Vienna from 2001, for Biota Holdings Ltd in Melbourne, Australia from 1999 in the area of respiratory viruses and Chiron Technologies in Melbourne from 1997. Darryl McConnell received his Bachelor of Science with First Class Honours in 1991 with Professor John Elix at the Australian National University in Canberra. He performed his PhD at the University of New South Wales in Sydney with Professor David Black for which he was awarded the Cornforth Medal for the best chemistry PhD thesis in Australia for that year. Following this he performed a 2 year Postdoctoral study at the University of Sydney with Professor Leslie Field in organometallic chemistry.
06 OCTOBER 2021 | 11AM (EDT) / 5PM (CEST)
Development of drugs that directly target the intrinsically disordered region of N-terminal domain of androgen receptor
Androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. All currently approved inhibitors of androgen receptor target its folded C-terminus ligand-binding domain. Resistance to these therapies is mediated by expression of constitutively active splice variants of androgen receptor that are truncated and lack a ligand-binding domain. Thus targeting the intrinsically disordered N-terminal domain of androgen receptor provides a novel therapeutic mechanism. Here we report our approach to the discovery and clinical development of small molecule inhibitors of this drug target previously considered to be “un-druggable”.
Dr. Sadar is a Professor of Pathology and Laboratory Medicine at the University of British Columbia and Distinguished Scientist in the Department of Genome Sciences at BC Cancer. Dr. Sadar’s research has focused on identifying mechanisms of transactivating the androgen receptor which is a therapeutic target for prostate cancer and other diseases. Uniquely her research has focused on developing therapies to the intrinsically disordered N-terminal domain of the androgen receptor which acts as a hub for essential protein-protein interactions required for its transcriptional activity. She has identified the first small molecule inhibitors that directly bind to the N-terminal domain of androgen receptor that has yielded compounds that have been taken into clinical trials. Her first-in-class compounds were granted a new stem class from the USAN council “-aniten”. Related work includes developing imaging agents with small molecules that bind to unique regions of the N-terminal domain of androgen receptor. Her current areas of research interest are concentrated predominantly on indications for prostate cancer and breast cancer.
Dr. Sadar is a co-founder, and past Director and Officer of ESSA Pharma Inc. (EPIX, NASDAQ). She has served in leadership positions such as President of the Society of Basic Urologic Research and the Y2017 Chair of the USA Army’s Department of Defence’s Programmatic Panel for their Prostate Cancer Research Program. Dr. Sadar has served on over 50 grant panels including 5 years on the NIH study session for Drug Discovery & Molecular Pharmacology.
03 NOVEMBER 2021 | 11AM (EDT) / 5PM (CEST)
Intrinsically Disordered Proteins in Neurodegenerative Diseases: A Computational Biophysicist’s Perspective
Intrinsically disordered proteins amyloid-β and α-synuclein are at the center of Alzheimer’s and Parkinson’s diseases. The main challenge in biophysics and biochemistry is the understanding of the fundamental principles governing intrinsically disordered protein misfolding and aggregation, which represent complex conditions and sensitive processes and these processes operate at various length and time-scales. Amyloid-β and α-synuclein misfolding andaggregation processes produce products ranging from dimers to fibrils. Aggregations of amyloid-β and/or α-synuclein have been studied mostly in the test tube where the conditions were far from physiological. Therefore, there is an urgent need to extend these studies to in vivo conditions where the formation of amyloid-β and α-synuclein is affected by numerous biochemical reactions. Such interactions need to be understood in detail to develop therapeutics because millions of people worldwide suffer from neurodegenerative diseases. Here, we describe recent advances in research on amyloid-β and α-synuclein formation from a physiochemical perspective, focusing on the physiological factors that influence amyloid-β and α-synuclein aggregation processes in Alzheimer’s and Parkinson’s diseases, respectively. A detailed emphasis is provided for computational biophysics studies that help us to understand the in vivo effects on amyloid-β and α-synuclein.
Orkid Coskuner-Weber grew up in Remscheid, Germany. Dr. Coskuner-Weber studied and received her Dr. rer-nat. degree in Chemistry from the Universität zu Köln in Köln, Germany. When Dr. Coskuner-Weber was a student at the Universität zu Köln, she visited University of Manchester Institute of Science and Technology (UMIST) and University of Amsterdam for further training in chemical engineering and physics. After her graduation, Dr. Coskuner-Weber worked as a postdoctoral scientist at Johns Hopkins University and Stanford University (Chemical and Biomolecular Engineering Department and EMSI/SSRL) in the United States.
Dr. Coskuner-Weber’s research attracted the interest of the government and consequently she worked for a national government laboratory (NIST) and linked her work to academia at the same time. Dr. Coskuner-Weber became a research assistant professor and then an assistant professor at George Mason University and University of Texas at San Antonio in the United States. In 2017, Dr. Coskuner-Weber took a faculty position at the Turkish-German University in Istanbul, Turkey for building up the Molecular Biotechnology Department. Dr. Coskuner-Weber became an associate professor and the department chair of Molecular Biotechnology. She has about 40 publications and worked on various national level projects in the United States and Turkey. Dr. Coskuner-Weber has designed and taught 10 different courses at the undergraduate and graduate levels.
09 FEBRUARY 2022 | 10AM (EDT) / 4PM (CEST)
Shifting Clouds: How Charges Impact IDP Dynamics
Intrinsically disordered proteins are tricky: their broad conformational ensemble is hard to grasp, and yet, specific changes to their chemical composition can make a huge difference. I will show, based on our molecular simulations, how the distribution of charges as naturally occurring across IDPs can tune the overall collapse propensity as well as local dynamics of IDPs. IDPs are prime targets of excessive phosphorylation by kinases, and we find that the added negative charges critically determine the swelling and collapse behavior of the IDP largely following simple electrostatic concepts. Such global and local conformational transitions are often critical for biological processes, and our simulations at atomistic and coarse-grain scale predict INCENP to be such a case. INCENP is a protein of the kinetochore which is vital for cell division. We show how its ~600 residue long IDP expands upon hyperphosphorylation, a mechanism likely to play a role in controlling the cell cycle. Phosphorylation and potentially other IDP modifications thus can push the conformational cloud of an IDP into new spaces, thereby controlling molecular interactions with proteins and likely small molecules.
Frauke Gräter is head of the research group “Molecular Biomechanics” at the Heidelberg Institute for Theoretical Studies (HITS) and Professor at Heidelberg University. She also currently acts as Scientific Director of HITS. She investigates how proteins have been designed to specifically respond to mechanical forces in the cellular environment or as a biomaterial, e.g. in the process of blood coagulation or in collagen fibers. To this end, her group uses and further develops various mult-scale molecular simulation techniques. She is recipient of the PRACE Ada Lovelace Award for High Performance Computing 2017 and has been awarded an ERC Consolidor Grant in 2021. As of 2021, she is Editorial Board Member of Biophysical Journal.
11 MAY 2022 | 11AM (EDT) / 5PM (CEST)
How Do Small Molecule Drugs Bind Intrinsically Disordered Proteins?
Intrinsically disordered proteins (IDPs), which represent ~40% of the human proteome, play crucial roles in a variety of biological pathways and biomolecular assemblies and have been implicated in many human diseases. IDPs do not fold into a well-defined three-dimensional structure under physiological conditions. Instead, they populate a dynamic conformational ensemble of rapidly interconverting structures. As a result, IDPs are extremely difficult to experimentally characterize in atomic detail and are currently considered “undruggable” by conventional structure-based drug design methods. Here, we describe recent progress in our efforts to integrate all-atom molecular dynamics (MD) computer simulations with biophysical experiments to characterize the interactions of IDPs with small molecule drugs and design more potent IDP inhibitors.
Paul Robustelli, PhD. is an assistant professor of chemistry at Dartmouth College, where his research focuses on the integration of computational and experimental methods to study dynamic and disordered proteins. Dr. Robustelli utilizes computer simulations and nuclear magnetic resonance (NMR) spectroscopy to model the conformational ensembles of intrinsically disordered proteins at atomic resolution to understand how small molecule drugs bind and inhibit disordered proteins and rationally design novel disordered protein inhibitors. Dr. Robustelli has made contributions to the development of physical models (“force fields”) that enable accurate simulations of disordered proteins and computational methods to integrate NMR data as restraints in molecular simulations.
Dr. Robustelli earned his B.A. in chemistry from Pomona College and his Ph.D. in chemistry from the University of Cambridge. Before joining the chemistry faculty at Dartmouth, Paul worked as a postdoctoral fellow at Columbia University and a scientist at D.E. Shaw Research.
01 JUNE 2022 | 11AM (EDT) / 5PM (CEST)
All-Atom Molecular Simulations of Disordered and Flexible Proteins
Molecular dynamics (MD) simulations are a useful tool to investigate the structure and dynamics of proteins because they can provide an all-atom view of their complex conformational landscapes. Using MD simulations, we are able to identify conformational states and their populations. I will present recent and ongoing simulation studies of disordered and flexible proteins. I will also present our recent efforts to track ordered waters in simulation using a new local alignment approach.
Dr. Sarah Rauscher is a computational biophysicist whose research addresses the challenging problem of understanding the structure and dynamics of intrinsically disordered proteins. She is currently an Assistant Professor of Physics at the University of Toronto Mississauga.