The Biochemical and Biophysical Systems Group

The Biochemical and Biophysical Systems Group’s scientists use cutting-edge, multi-scale, in silico simulations to tackle problems in biology. We use a wide range of computational biology methods that employ LLNL’s high-performance computing resources to simulate systems from sub-atomic scale to population level. These methods include atomistic and coarse-grained molecular dynamics, quantum simulations, constraint-based genome-scale simulations, reaction-transport dynamic simulations, and agent-based, whole-organ, and pharmacokinetics/pharmacodynamics models. We develop new computational methods to describe and predict biological systems. In addition, we combine experimental efforts with physics-based simulations and statistical and machine-learning models to accelerate the design and development of safe and effective therapeutics. Overall, we seek predictive understanding of protein-mediated processes related to critical missions of LLNL, including bioenergy, medical countermeasures, and new materials. 

Recent Publications

Discovery of Small-molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline
Edmond Y. Lau, Oscar A. Negrete, W. F. Drew Bennett, Brian J. Bennion, Monica Borucki, Feliza Bourguet, Aidan Epstein, Magdalena Franco, Brooke Harmon, Stewart He, Derek Jones, Hyojin Kim, Daniel Kirshner, Victoria Lao, Jacky Lo, Kevin McLoughlin, Richard Mosesso, Deepa K. Murugesh, Edwin A. Saada, Brent Segelke, Maxwell A. Stefan, Garrett A. Stevenson, Marisa W. Torres, Dina R. Weilhammer, Sergio Wong, Yue Yang, Adam Zemla, Xiaohua Zhang, Fangqiang Zhu, Jonathan E. Allen, Felice C. Lightstone
Frontiers in Molecular Biosciences (2021) 8 644.

Enabling Rapid COVID-19 Small Molecule Drug Design Through Scalable Deep Learning of Generative Models
Sam Ade Jacobs, Tim Moon, Kevin McLoughlin, Derek Jones, David Hysom, Dong H. Ahn, John Gyllenhaal, Pythagoras Watson, Felice C. Lightstone, Jonathan E. Allen, Ian Karlin, Brian Van Essen
International Journal of High Performance Computing Applications (2021) Accepted.

Machine Learning Based Dynamic-Importance Sampling for Adaptive Multiscale Simulations
Harsh Bhatia, Timothy S. Carpenter, Helgi I. Ingolfsson, Gautham Dharuman, Piyush Karande, Shusen Liu, Tomas Oppelstrup, Chris Neale, Felice C. Lightstone, Brian Van Essen, James N. Glosli, Peer-Timo Bremer
Nature Machine Intelligence​ (2021) https://doi.org/10.1038/s42256-021-00327-w.

Improved Protein–Ligand Binding Affinity Prediction with Structure-Based Deep Fusion Inference
Derek Jones, Hyojin Kim, Xiaohua Zhang, Adam Zemla, Garrett Stevenson, W. F. Drew Bennett, Daniel Kirshner, Sergio E. Wong, Felice C. Lightstone, and Jonathan E. Allen
Journal of Chemical Information and Modeling (2021) 61, 4, 1583–1592.

Comprehensive characterization of protein-protein interaction network perturbations by human disease mutations
Feixiong Cheng, Junfei Zhao, Yang Wang, Weiqiang Lu, Zehui Liu, Yadi Zhou, William Martin, Ruisheng Wang, Jin Huang, Tong Hao, Hong Yue, Jing Ma, Yuan Hou, Jessica Castrillon, Jiansong Fang, Justin Lathia, Ruth A. Keri, Felice C. Lightstone, Elliott Marshall Antman, Raul Rabadan, David E. Hill, Charis Eng, Marc Vidal, Joseph Loscalzo
Nature Genetics​ (2021) 53, 342–353.

Atomistic Characterization of Gramicidin Channel Formation
Delin Sun, Stewart He, W. F. Drew Bennett, Camille L. Bilodeau, Olaf S. Andersen, Felice C. Lightstone, Helgi I. Ingolfsson
J. Chem. Theory Comput.​ (2021) 17, 1, 7–12.

Flux: Overcoming Scheduling Challenges for Exascale Workflows
Dong H. Ahn, Ned Bass, Albert Chu, Jim Garlick, Mark Grondona, Stephen Herbein, Helgi I. Ingólfsson, Joseph Koning, Tapasya Patki, Thomas R. W. Scogland, Becky Springmeyer and Michela Taufer
Future Generation Computer Systems ​ (2020) 110, 202-213.

Assessing the Perturbing Effects of Drugs on Lipid Bilayers using Gramicidin Channel-Based in Silico and in Vitro Assays
Delin Sun, Thasin A. Peyear, W. F. Drew Bennett, Matthew Holcomb, Stewart He, Fangqiang Zhu, Felice C. Lightstone, Olaf S. Andersen, and Helgi I. Ingólfsson
Journal of Medicinal Chemistry (2020) 63, 11809-11818.

Predicting Small Molecule Transfer Free Energies by Combining Molecular Dynamics Simulations and Deep Learning
W. F. Drew Bennett, Stewart He, Camille L. Bilodeau, Derek Jones, Delin Sun, Hyojin Kim, Jonathan E. Allen, Felice C. Lightstone, Helgi I. Ingolfsson
Journal of Chemical Information and Modeling (2020) 60, 11, 5375-5381.

Capturing Biologically Complex Tissue-Specific Membranes at Different Levels of Compositional Complexity
Helgi I. Ingólfsson, Harsh Bhatia, Talia Zeppelin, W. F. Drew Bennett, Kristy A. Carpenter, Pin-Chia Hsu, Gautham Dharuman, Peer-Timo Bremer, Birgit Schiøtt, Felice C. Lightstone, and Timothy S. Carpenter
Journal of Physical Chemistry B (2020) 124, 36, 7819–7829.

Simulations of asymmetric membranes illustrate cooperative leaflet coupling and lipid adaptability
Madison Blumer, Sophia Harris, Mengzhe Li, Luis Martinez, Michael Untereiner, Peter N. Saeta, Timothy S. Carpenter, Helgi I. Ingólfsson and W. F. Drew Bennett.
Frontiers Cell Developmental Biology (2020) 8, 575.

ddcMD:A Fully GPU-accelerated Molecular Dynamics Program for the Martini Force Field
Xiaohua Zhang, Shiv Sundram, Tomas Oppelstrup, Sara I. L. Kokkila-Schumacher, Timothy S. Carpenter, Helgi I. Ingólfsson, Frederick H. Streitz, Felice C. Lightstone, James N. Glosli
Journal of Chemical Physics (2020) 153, 045103.

Binding Affinity Prediction by Pairwise Function Based on Neural Network
​Fangqiang Zhu, Xiaohua Zhang, Jonathan E. Allen, Derek Jones, Felice C. Lightstone
Journal of Chemical Information and Modeling (2020) 60, 2766-2772.

Decoupling copolymer, lipid and carbon nanotube interactions in hybrid, biomimetic vesicles
Joshua A. Hammons, Helgi I. Ingólfsson, Jonathan R. I. Lee, Timothy S. Carpenter, Jeremy Sanborn, Ramya Tunuguntla, Yun-Chiao Yao, Thomas M. Weiss, Aleksandr Noy, Tony Van Buuren.  
Nanoscale (2020) 12, 6545-6555.

In Silico Insights into Protein-protein Interaction Disruptive Mutations in the PCSK9-LDLR Complex
William R. Martin, Felice C. Lightstone, and Feixiong Cheng
International Journal of Molecular Sciences (2020) 21(5), 1550.

Microsecond molecular dynamics simulations of proteins using a quasi-equilibrium solvation shell model
Victor Ovchinnikov, Simone Conti, Edmond Y. Lau, Felice C. Lightstone, and Martin Karplus
Journal of Chemical Theory and Computation (2020) 16, 3, 1866–1881.

Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior
Debanjan Goswami, De Chen, Yue Yang, Prabhakar R. Gudla, John Columbus, Karen Worthy, Megan Rigby, Madeline Wheeler, Suman Mukhopadhyay, Katie Powell, William Burgan, Vanessa Wall, Dominic Esposito, Dhirendra Simanshu, Felice C. Lightstone, Dwight V. Nissley, Frank McCormick, Thomas Turbyville
eLife (2020) 9: e47654.

A Massively Parallel Infrastructure for Adaptive Multiscale Simulations: Modeling RAS Initiation Pathway for Cancer
Frank Di Natale, Harsh Bhatia, Timothy S. Carpenter, Chris Neale, Sara Kokkila Schumacher, Tomas Oppelstrup, Liam Stanton, Xiaohua Zhang, Shiv Sundram, Thomas R. W. Scogland, Gautham Dharuman, Michael P. Surh, Yue Yang, Claudia Misale, Lar Schneidenbach, Carlos Costa, Changhoan Kim, Bruce D’Amora, Sandrasegharam Gnanakaran, Dwight V. Nissley, Frederick Streitz, Felice C. Lightstone, Peer-Timo Bremer, James N. Glosli, Helgi I. Ingólfsson
SC '19: Proceedings of the International Conference for High Performance Computing, Networking, Storage and Analysis (2019) 57, 1-16 (won Best Paper).

Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness
Delin Sun, Thasin A. Peyear, W. F. Drew Bennett, Olaf S. Andersen, Felice C. Lightstone, Helgi I. Ingólfsson
Biophysical Journal (2019) 117, 1831–1844.

MemSurfer: A Tool for Robust Computation and Characterization of Curved Membranes.
Harsh Bhatia, Helgi I. Ingólfsson, Timothy S. Carpenter, Felice C. Lightstone, and Peer-Timo Bremer
Journal of Chemical Theory and Computation (2019) 15, 11, 6411-6421.

Multiscale Modeling and Simulation Approaches to Lipid–Protein Interactions
R.G. Huber, T.S. Carpenter, N. Dube, D.A. Holdbrook, H.I. Ingólfsson, W.A. Irvine, J.K. Marzinek, F. Samsudin, J.R. Allison, S. Khalid, and P.J. Bond 
In: Kleinschmidt J. (eds) Lipid-Protein Interactions. Methods in Molecular Biology, vol 2003 (2019). Humana, New York, NY.

System-level analysis of metabolic trade-offs during anaerobic photoheterotrophic growth in Rhodopseudomonas palustris
Ali Navid, Yongqin Jiao, Sergio E. Wong, Jennifer Pett-Ridge
BMC Bioinformatics (2019) 20:233.

Combining multiple functional annotation tools increases coverage of metabolic annotation
Marc Griesemer, Jeffrey A. Kimbrel, Carol E. Zhou, Ali Navid, Patrik D’haeseleer
BMC Genomics (2018) 19, (1) 948.

Structural control of nonnative ligand binding in engineered mutants of phosphoenolpyruvate carboxykinase
Henry Yue Hin Tang, David S. Shin, Gregory L. Hura, Yue Yang, Xiaoyu Hu, Felice C. Lightstone, Matthew D. McGee, Hal S. Padgett, Steven M. Yannone, and John A. Tainer
Biochemistry (2018) 57, (48) pp 6688–6700.

Cholesterol flip-flop impacts domain registration in plasma membrane models
Sebastian Thallmair, Helgi I. Ingólfsson and Seiwert J. Marrink
J. Phys. Chem. Lett. (2018) 9, (18) 5527-5533.

Capturing Phase Behavior of Ternary Lipid Mixtures with a Refined Martini Coarse-Grained Force Field
Timothy S. Carpenter, Cesar A. López, Christopher Neale, Cameron Montour, Helgi Ingólfur Ingólfsson, Francesco Di Natale, Felice C. Lightstone, and Sandrasegaram Gnanakaran
Journal of Chemical Theory and Computation (2018) 14, (11) 6050-6062.

Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies
Jeffrey M. Witkin, Ryan A. Shenvi, Xia Li, Scott D. Gleason, Julie Weiss, Denise Morrow, John T. Catow, Mark Wakulchik, Masaki Ohtawa, Hai-Hua Lu, Michael D. Martinez, Jeffrey M. Schkeryantz, Timothy S. Carpenter, Felice C. Lightstone, Rok Cerne
Biochemical Pharmacology (2018) 155, 61-70.

Lipid composition dictates serum stability of reconstituted high-density lipoproteins: implications for in vivo applications
Sean F. Gilmore, Timothy S. Carpenter, Helgi I. Ingolfsson, Sandra K. G. Peters, Paul T. Henderson, Craig D. Blanchette, Nicholas O. Fischer
Nanoscale (2018) 10, 7420-7430.

Efficient Computational Modeling of Human Ventricular Activation and Its Electrocardiographic Representation: A Sensitivity Study
Johathan P. Cranford, Thomas J. O’Hara, Christopher T. Villongco, Omar M. Hafez, Robert C. Blake, Joseph Loscalzo, Jean-Luc Fattebert, David F. Richards, Xiaohua Zhang, James N. Glosli, Andrew D. McCulloch, David E. Krummen, Felice C. Lightstone, Sergio E. Wong
Cardiovascular Engineering and Technology (2018) 9, Online First.

Computational lipidomics of the neuronal plasma membrane
Helgi I. Ingólfsson, Timothy S. Carpenter, Harsh Bhatia, Peer-Timo Bremer, Siewert J. Marrink, Felice C. Lightstone
Biophysics Journal (2017) 113 (10), 2271-2280.

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs 
M. A Malfatti, H. A. Enright, N. A. Be, E. A. Kuhn, S. Hok, M. W. NcNerney, V. Lao, T. H. Nguyen, F. C. Lightstone, T. S. Carpenter, B. J. Bennion, C. A. Valdez
Chemico-Biological Interactions (2017) 277, 159-167.

Simultaneous electrical recording of cardiac electrophysiology and contraction on chip
Fang Qian, Chao Huang, Yi-Dong Lin, Anna N. Ivanovskaya, Thomas J. O'Hara, Ross H. Booth, Cameron J. Creek, Heather A. Enright, David A. Soscia, Anna M. Belle, Ronglih Liao, Felice C. Lightstone, Kristen S. Kulp and Elizabeth K. Wheeler
Lab on a Chip (2017) 17, 1732-1739.

Predicting a Drug’s Membrane Permeability: A Computational Model Validated With In Vitro Permeability Assay Data
Brian J. Bennion, Nicholas A. Be, Margaret Windy McNerney, Victoria Lao, Emma M. Carlson, Carlos A. Valdez, Michael A. Malfatti, Heather A. Enright, Tuan H Nguyen, Felice C Lightstone, and Timothy S. Carpenter
J. Phys. Chem. B (2017) 121 (20), 5228-5237.

Re-directing bacterial microcompartment systems to enhance recombinant expression of lysis protein E from bacteriophage ϕX174 in Escherichia coli
Mimi C. Yung, Feliza A. Bourguet, Timothy S. Carpenter and Matthew A. Coleman
Microb. Cell Fact. (2017) 16 (71).

A Comprehensive Docking and MM/GBSA Rescoring Study of Ligand Recognition upon Binding Antithrombin
Xiaohua Zhang, Horacio Perez-Sanchez, and Felice C. Lightstone
Current Topics in Medicinal Chemistry (2017) 17, 1-9.