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Principal Investigator: Alexander Dickson
Organization: MICHIGAN STATE UNIVERSITY
Fiscal Year: 2023
Award: $327,537
Funding agency: National Institute of General Medical Sciences
Project Summary
Biology at the nanoscale is driven by molecular recognition. Cells are lined with receptors that recognize a
myriad of biomolecules and transmit signals to the cell interior. This forms the basis of cell-cell communication
that allows multicellular organisms to thrive. An understanding of molecular recognition is tremendously
important for human health, as it underlies our immune system’s response to threats from viruses, bacteria and
cancer cells. Unfortunately, these recognition processes are often much more complicated than the canonical
“lock-and-key” paradigm. Many neuropeptides and peptide hormones are dozens of residues in length and can
exhibit tremendous structural plasticity. The study of molecular recognition in such dynamic systems is a
challenge, as only a limited understanding of the interactions can be gleaned from structural approaches alone.
Computational molecular dynamics (MD) simulation allows us to view complex biomolecular systems in
atomic detail, allowing us to compute binding and unbinding rates, and to study their molecular determinants. A
well-known drawback of MD is the difficulty of exploring conformational landscapes without getting trapped in
local free energy minima. The PI (Dickson) has over a decade of experience developing new methods for
tackling this problem, which are able to calculate transition rates in complex systems. Particularly, the REVO
method (“Reweighting Ensembles by Variation Optimization”) has shown success on unbinding pathways of
drug-like ligands with mean first passage times up to 34 minutes, which is billions of times beyond the typical
reach of straightforward MD. This is done without applying biasing forces to the system or making any
assumptions about equilibrium conditions. REVO is essentially an evolutionary algorithm in trajectory space,
where a large group of trajectories are run in parallel, and outlier trajectories are identified using a
measurement of distance to other ensemble members. These outliers are “cloned”, which increases the
probability of seeing long-timescale events happen, even in short-time trajectories.
The proposed work will augment this method with recent advances in the automatic detection of slow
collective variables (or “CVs”). The VAMPnet (“Variational Approach for Markov Processes”) approach will be
used to detect groups of CVs to use in the REVO distance calculation. A method for iteratively improving the
accuracy of rate calculations (“Asynchronous weighted ensemble”) is also proposed. Together these
developments will constitute a powerful tool for studying long-timescale events in complex biomolecular
systems that will be made freely available to other researchers. Through collaborations with experimental
partners, this method will be applied to reveal the molecular mechanisms of: i) peptide signaling for a class-B
GPCR (Aim 2), and ii) specific recognition of bacterial LPS by a phage tail-spike protein (Aim 3). These
mechanisms will inform the design of new molecules with potential therapeutic applications.
Terms: <Affect><Algorithms><Award><Bacteria><Bacteriophages><Binding><Binding Proteins><Binding Sites><Biological Function><Biological Process><Biology><CRLR protein><Carbohydrates><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Line><Cell Signaling><Cell Wall><Cell surface><Cell-to-Cell Interaction><CellLine><Cells><Chemicals><Collaborations><Combining Site><Communities><Complex><Computational algorithm><Computer software><Computing Methodologies><DNA Molecular Biology><Data Set><Detection><Development><Drugs><Endocrine Gland Secretion><Equilibrium><Event><Evolution><Exhibits><External Domain><Extracellular Domain><Free Energy><Freedom><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Glean><Health><Hormones><Human><Immune response><Immunological response><Intracellular Communication and Signaling><Investigators><Kinetics><Knowledge><Learning><Length><Liberty><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Lipopolysaccharides><Malignant Cell><Markov Chains><Markov Process><Measurement><Medication><Methodology><Methods><Modeling><Modern Man><Molecular><Molecular Biology><Molecular Computations><Molecular Configuration><Molecular Conformation><Molecular Dynamics Simulation><Molecular Interaction><Molecular Stereochemistry><Motion><NIH><National Institutes of Health><Nature><Neurohumor Receptors><Neuromediator Receptors><Neuropeptides><Neuroregulator Receptors><Neurotransmitter Receptor><Organism><Parents><Pathway interactions><Peptide Hormone Gene><Peptide Receptor><Peptide Signal Sequences><Peptides><Phages><Pharmaceutic Preparations><Pharmaceutical Preparations><Probability><Process><Protein Binding><Protein Conformation><Proteins><Reactive Site><Receptor Protein><Research Personnel><Researchers><Role><Running><S flexneri><S. flexneri><Sampling><Serotyping><Shigella flexneri><Signal Peptide><Signal Sequences><Signal Transduction><Signal Transduction Systems><Signaling><Software><Specificity><Strains Cell Lines><System><Therapeutic><Therapeutic Hormone><Time><Transmission><Uncertainty><United States National Institutes of Health><Variant><Variation><Virion><Virus><Virus Particle><Work><antagonism><antagonist><bacterial virus><bacteriophage tailspike protein><balance><balance function><biological signal transduction><biological systems><bound protein><calcitonin receptor-like receptor><cancer cell><chemical reaction><cofactor><computational methodology><computational methods><computer algorithm><computer based method><computer methods><computing method><conformation><conformational><conformational state><conformationally><conformations><cultured cell line><design><designing><developmental><doubt><drug/agent><dynamic system><dynamical system><experience><extracellular><flexibility><flexible><host response><human pathogen><immune system response><immunoresponse><improved><innovate><innovation><innovative><insight><interest><living system><member><migraine therapy><migraine treatment><molecular dynamics><molecular recognition><mutant><nano meter scale><nano meter sized><nano scale><nano second><nanometer scale><nanometer sized><nanoscale><nanosecond><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><parent><pathway><peptide hormone><protein signal sequence><receptor><receptor-activity-modifying protein><simulation><social role><success><tailspike protein><tool><transmission process>