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

PDBspheres-a method for finding 3D similarities in local regions in proteins
Adam Zemla, Jonathan E Allen, Dan Kirshner, Felice C Lightstone
Nucleic Acids Research (2022) Accepted.

Scalable Composition and Analysis Techniques for Massive Scientific Workflows
Dong H. Ahn, Xiaohua Zhang, Jeffrey Mast, Stephen Herbein, Francesco Di Natale, Dan Kirshner, Sam Ade Jacobs, Ian Karlin, Daniel J. Milroy, Bronis De Supinski, Brian Van Essen, Jonathan Allen, Felice C. Lightstone
eScience ’22 (2022) Accepted.
Won Best Paper

Deep Generative Molecular Design Reshapes Drug Discovery
Xiangxiang Zeng, Fei Wang, Yuan Luo, Seung-gu Kang, Jian Tang, Felice C. Lightstone, Evandro F. Fang, Wendy Cornell, Ruth Nussinov, Feixiong Cheng
Cell Reports Medicine (2022) 3, 100794.

Exploring CRD mobility during RAS/RAF engagement at the membrane
Kien Nguyen, Cesar A. López, Chris Neale, Que N. Van, Timothy S. Carpenter, Francesco Di Natale, Timothy Travers, Timothy H. Tran, Albert H. Chan, Harsh Bhatia, Peter H. Frank, Marco Tonelli, Xiaohua Zhang, Gulcin Gulten, Tyler Reddy, Violetta Burns, Tomas Oppelstrup, Nick Hengartner, Dhirendra K Simanshu, Peer-Timo Bremer, De Chen, James N. Glosli, Rebika Shrestha, Thomas Turbyville, Frederick H. Streitz, Dwight V. Nissley, Helgi I. Ingólfsson, Andrew G. Stephen, Felice C. Lightstone, Sandrasegaram Gnanakaran
Biophysical Journal (2022) 121, 19, 3630.

A Biology-Informed Similarity Metric for Simulated Patches of Human Cell Membrane
Harsh Bhatia, Jayaraman J. Thiagarajan, Rushil Anirudh, T. S. Jayram, Tomas Oppelstrup, Helgi I. Ingólfsson, Felice C. Lightstone, Peer-Timo Bremer
Machine Learning: Science and Technology (2022) 3 (3), 2632-2153.

Bacterial exometabolites influence Chlamydomonas cell cycle and double algal productivity
Miriam Windler, Rhona Stuart, Joerg S. Deutzmann, Xavier Mayali, Ali Navid, Patrik D’haeseleer, Oana E. Marcu, Mary Lipton, Carrie Nicora, Alfred M. Spormann
FEMS Microbiology Ecology (2022) 98, 1.

On the Rapid Calculation of Binding Affinities for Antigen and Antibody Design and Affinity Maturation Simulations
Simone Conti, Edmond Y. Lau, and Victor Ovchinnikov (2022) 
Antibodies (2022) 11(3), 51.

Asynchronous Reciprocal Coupling of Martini 2.2 Coarse-Grained and CHARMM36 All-Atom Simulations in an Automated Multiscale Framework
Cesar A. Lopez, Xiaohua Zhang, Fikret Aydin, Rebika Shrestha, Que N. Van, Christopher B. Stanley, Timothy S. Carpenter, Kien Nguyen, Lara A. Patel, De Chen, Violetta Burns, Nicolas W. Hengartner, Tyler J. E. Reddy, Harsh Bhatia, Francesco Di Natale, Timothy H. Tran, Albert H. Chan, Dhirendra K. Simanshu, Dwight V. Nissley, Frederick H. Streitz, Andrew G. Stephen, Thomas J. Turbyville, Felice C. Lightstone, Sandrasegaram Gnanakaran, Helgi I. Ingolfsson, Chris Neale
Journal of Chemical Theory and Computation (2022) 18 (8), 5025-5045..

Large-scale application of free energy perturbation calculations for antibody design
Fangqiang Zhu, Feliza A. Bourguet, W. F. Drew Bennett, Edmond Y. Lau, Kathryn T. Arrildt, Brent W. Segelke, Adam T. Zemla, Thomas A. Desautels, and Daniel M. Faissol
Scientific Reports (2022) 12, 12489.

Bacterial Membranes Are More Perturbed by the Asymmetric Versus Symmetric Loading of Amphiphilic Molecules
W. F. Drew Bennett, Stephen J. Fox, Delin Sun, and C. Mark Maupin
Membranes (2022) 12, 4, 350

Regulation of Gramicidin Channel Function Solely by Changes in Lipid Intrinsic Curvature
Andreia M. Maer, Radda Rusinova, Lyndon L. Providence, Helgi I. Ingólfsson, Shemille A. Collingwood, Jens A. Lundbæk and Olaf S. Andersen
Frontiers in Physiology (2022) 13:836789.

Interpretable artificial intelligence and exascale molecular dynamics simulations to reveal kinetics: Applications to Alzheimer's disease
William Martin, Gloria Sheynkman, Felice C Lightstone, Ruth Nussinov, Feixiong Cheng
Current Opinion in Structural Biology (2022) 72, 103.

Multiframe Imaging of Micron and Nanoscale Bubble Dynamics
Garth C. Egan, Edmond Y. Lau, and Eric Schwegler
Nano Letters (2022) 22 (3), 1053-1058

Machine learning–driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins
Helgi I. Ingólfsson, Chris Neale, Timothy S. Carpenter, Rebika Shrestha, Cesar A. López, Timothy H. Tran, Tomas Oppelstrup, Harsh Bhatia, Liam G. Stanton, Xiaohua Zhang, Shiv Sundram, Francesco Di Natale, Animesh Agarwal, Gautham Dharuman, Sara I. L. Kokkila Schumacher, Thomas Turbyville, Gulcin Gulten, Que N. Van, Debanjan Goswami, Frantz Jean-Francois, Constance Agamasu, De Chen, Jeevapani J. Hettige, Timothy Travers, Sumantra Sarkar, Michael P. Surh, Yue Yang, Adam Moody, Shusen Liu, Brian C. Van Essen, Arthur F. Voter, Arvind Ramanathan, Nicolas W. Hengartner, Dhirendra K. Simanshu, Andrew G. Stephen, Peer-Timo Bremer, S. Gnanakaran, James N. Glosli, Felice C. Lightstone, Frank McCormick, Dwight V. Nissley, and Frederick H. Streitz
Proceedings of the National Academy of Sciences (2022) 119 (1) e2113297119.

Generalizable coordination of large multiscale workflows: challenges and learnings at scale
Harsh Bhatia, Francesco Di Natale, Joseph Y. Moon, Xiaohua Zhang, Joseph R. Chavez, Fikret Aydin, Chris Stanley, Tomas Oppelstrup, Chris Neale, Sara Kokkila Schumacher, Dong H. Ahn, Stephen Herbein, Timothy S. Carpenter, Sandrasegaram Gnanakaran, Peer-Timo Bremer, James N Glosli, Felice C. Lightstone, Helgi I. Ingólfsson
SC '21: Proceedings of the International Conference for High Performance Computing, Networking, Storage and Analysis (2021) Article No.: 10, 1-16.

High-throughput virtual screening of small molecule inhibitors for SARS-CoV-2 protein targets with deep fusion models
Garrett A. Stevenson, Derek Jones, Hyojin Kim, W. F. Drew Bennett, Brian J. Bennion, Monica Borucki, Feliza Bourguet, Aidan Epstein, Magdalena Franco, Brooke Harmon, Stewart He, Max P. Katz, Daniel Kirshner, Victoria Lao, Edmond Y. Lau, Jacky Lo, Kevin McLoughlin, Richard Mosesso, Deepa K. Murugesh, Oscar A. Negrete, Edwin A. Saada, Brent Segelke, Maxwell Stefan, Marisa W. Torres, Dina Weilhammer, Sergio Wong, Yue Yang, Adam Zemla, Xiaohua Zhang, Fangqiang Zhu, Felice C. Lightstone, Jonathan E. Allen
SC '21: Proceedings of the International Conference for High Performance Computing, Networking, Storage and Analysis (2021) Article No.: 74, 1–13.

Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
Brian J. Bennion, Michael A. Malfatti, Nicholas A. Be, Heather A. Enright, Saphon Hok, C. Linn Cadieux, Timothy S. Carpenter, Victoria Lao, Edward A. Kuhn, M. Windy McNerney, Felice C. Lightstone, Tuan H. Nguyen, and Carlos A. Valdez
Scientific Reports (2021) 11, 15567.

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) 35(5), 469–482.

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) 3, 401–409.  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.