Science

Dr. Salsbury’s March 2023 APS Talk

Here are some selected themes of research, with some papers reflecting multiple themes, in the Salsbury Group:

Understanding the relationship between dynamics and function, in particular the notion of dynamic or generalized allostery. This is currently our largest focus. Some representative recent papers include:

  1. Wu D, Xiao J, Salsbury FR Jr. Light Chain Mutation Effects on the Dynamics of Thrombin. J Chem Inf Model. 2021 Feb 22;61(2):950-965. doi: 10.1021/acs.jcim.0c01303. Epub 2021 Jan 15.PMID: 33450154
  2. Xiao J, Salsbury FR. Na(+)-binding modes involved in thrombin’s allosteric response as revealed by molecular dynamics simulations, correlation networks, and Markov modeling. Phys Chem Chem Phys.2019 Feb 20;21(8):4320-4330. doi:10.1039/c8cp07293k. PubMed PMID: 30724273.
  3. Xiao J, Melvin RL, Salsbury FR Jr. Probing light chain mutation effects on thrombin via molecular dynamics simulations and machine learning. J Biomol Struct Dyn. 2019 Mar;37(4):982-999. doi: 10.1080/07391102.2018.1445032. Epub 2018 Mar 2. PubMed PMID: 29471734; PubMed Central PMCID:PMC6207482.
  4. Melvin RL, Thompson WG, Godwin RC, Gmeiner WH, Salsbury FR. MutSα’s Multi-Domain AllostericResponse to Three DNA Damage Types Revealed by Machine Learning. Front. Phys., 30 March 2017 |https://doi.org/10.3389/fphy.2017.00010
  5. Godwin RC, Melvin RL, Gmeiner WH, Salsbury FR Jr. Binding Site Configurations Probe the Structure and Dynamics of the Zinc Finger of NEMO (NF-κB Essential Modulator). Biochemistry. 2017 Jan 31;56(4):623-633. doi: 10.1021/acs.biochem.6b00755. PubMed PMID: 28035815.

A focus that is re-emerging is in method development; most recently in the application of machine learning and newer statistical methods. This started as a focus on improving implicit solvent models so that they would be more rigorous and accurate and to improve the application of simulation methods to more useful biomedical systems. Currently, we are focused on applying better and more modern statistical analysis methods to the analysis of molecular dynamics trajectories and the application of machine learning techniques to simulations and drug screening. Some representative papers include:

  1. Xiao J, Salsbury FR. Na(+)-binding modes involved in thrombin’s allosteric response as revealed by molecular dynamics simulations, correlation networks, and Markov modeling. Phys Chem Chem Phys.2019 Feb 20;21(8):4320-4330. doi:10.1039/c8cp07293k. PubMed PMID: 30724273.
  2. Xiao J, Melvin RL, Salsbury FR Jr. Probing light chain mutation effects on thrombin via molecular dynamics simulations and machine learning. J Biomol Struct Dyn. 2019 Mar;37(4):982-999. doi: 10.1080/07391102.2018.1445032. Epub 2018 Mar 2. PubMed PMID: 29471734; PubMed Central PMCID:PMC6207482.
  3. Melvin RL, Thompson WG, Godwin RC, Gmeiner WH, Salsbury FR. MutSα’s Multi-Domain AllostericResponse to Three DNA Damage Types Revealed by Machine Learning. Front. Phys., 30 March 2017 |https://doi.org/10.3389/fphy.2017.00010
  4. M.S. Lee, F. R. Salsbury, Jr, and C.L. Brooks, III, New and Novel Generalized Born Methods, J. Chem. Phys., 116 (24), 10606-10614 (2002).
  5. M. S. Lee, F. R. Salsbury, Jr., and C. L. Brooks, III, Constant pH-molecular Dynamics using Continuous Titration Coordinate, Proteins: Structure, Function, and Bioinformatics, 56 (4):738-752 (2004).
  6. Melvin RL, Godwin RC, Xiao J, Thompson WG, Berenhaut KS, Salsbury FR Jr. Uncovering Large-Scale Conformational Change in Molecular Dynamics without Prior Knowledge. J Chem Theory Comput. 2016 Dec 13;12(12):6130-6146. PubMed PMID: 27802394.
  7. Melvin RL, Xiao J, Berenhaut KS, Godwin RC, Salsbury FR. Using correlated motions to determine sufficient sampling times for molecular dynamics. Phys Rev E. 2018 Aug;98(2-1):023307. doi: 10.1103/PhysRevE.98.023307. PubMed PMID:30253618; PubMed Central PMCID: PMC6325644.

Our research in general is motivated by drug discovery and development. Some of that research is more explicit in that regard. Some of that is not published and some representative more recent papers include:

  1. Hemphill WO, Simpson SR, Liu M, Salsbury FR Jr, Hollis T, Grayson JM, Perrino FW. TREX1 as a Novel Immunotherapeutic Target. Front Immunol. 2021 Apr 1;12:660184. doi: 10.3389/fimmu.2021.660184. eCollection 2021.PMID: 33868310 
  2. Melvin RL, Gmeiner WH, Salsbury All-atom MD indicates ion-dependent behavior of therapeutic DNA polymer. FR.Phys Chem Chem Phys. 2017 Aug 23;19(33):22363-22374. doi: 10.1039/c7cp03479b.PMID: 28805211 
  3. Melvin RL, Gmeiner WH, Salsbury FR Jr. All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10 J Phys Chem B. 2016 Oct 6;120(39):10269-10279. doi: 10.1021/acs.jpcb.6b07753. Epub 2016 Sep 21.PMID: 27606431 
  4. Godwin RC, Melvin RL, and Salsbury FR. Molecular Dynamics Simulations in Computer-Aided Drug Discovery. Methods in Pharmacology and Toxicology. 2016:1-30
  5. Stuart CH, Horita DA, Thomas MJ, Salsbury FR Jr, Lively MO, Gmeiner WH .Site-specific DNA-doxorubicin conjugates display enhanced cytotoxicity to breast cancer cells Bioconjug Chem. 2014 Feb 19;25(2):406-13. doi: 10.1021/bc4005427. Epub 2014 Feb 6.
  6. Abdel Hafez EM, Diamanduros A, Negureanu L, Luy Y, Bean JH, Zielke K, Crowe B, Vasilyeva A, Clodfelter JE, Aly OM, Abuo-Rahma GE, Scarpinato KD, Salsbury FR Jr, King SB. Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment. Mol Cancer Biol. 2013;1(1):44.

Studying the effects of less abundant elements, in particular zinc and fluorine. In particular, we have studied zinc in proteins in the context of metallo-beta-lactamases and in the context of zinc fingers; the questions have centered around how does the zinc perturb the mechanical and conformational propensities of proteins, and how do ligands bind zincs. We have also studies how zinc interacts with FdU-substituted DNA and how that interaction changes with the binding of netropsin. These studies have also led us to study how FdU perturbs the dynamics of DNA, how FdU itself behaves as a polymer in the presence or absence of different ions. Representative papers include:

  1. Melvin RL, Gmeiner WH, Salsbury FR Jr. All-Atom MD Predicts Magnesium-Induced Hairpin in Chemically Perturbed RNA Analog of F10 Therapeutic. J Phys Chem B. 2017 Aug 24;121(33):7803-7812.
  2. S. Ghosh, F. Salsbury, D. Horita, and W. Gmeiner, Zn2+ Selectively Stabilizes FdU-Substituted DNA Through a Unique Major Groove Binding Motif, Nucleic Acids Research  39:4490-98 (2011).
  3. Melvin RL, Gmeiner WH, Salsbury FR. All-atom MD indicates ion-dependent behavior of a therapeutic DNA polymer. Phys Chem Chem Phys. 2017 Aug 23;19(33):22363-22374. doi: 10.1039/c7cp03479b.PubMed PMID: 28805211; PubMed Central PMCID: PMC5600158.
  4. Ghosh S, Salsbury FR Jr, Horita DA, Gmeiner WH. Cooperative stabilization of Zn(2+): DNA complexes through netropsin binding in the minor groove of FdU-substituted DNA. J Biomol Struct Dyn. 2013;31(11):1301-10. doi: 10.1080/07391102.2012.732343. PubMed PMID: 23153072; PubMed Central PMCID: PMC3825453.
  5. Godwin RC, Melvin RL, Gmeiner WH, Salsbury FR Jr. Binding Site Configurations Probe the Structure and Dynamics of the Zinc Finger of NEMO (NF-κB Essential Modulator). Biochemistry. 2017 Jan 31;56(4):623-633. doi: 10.1021/acs.biochem.6b00755. PubMed PMID: 28035815.
  6. Melvin RL, Gmeiner WH, Salsbury FR Jr. All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10. J Phys Chem B. 2016 Oct 6;120(39):10269-10279. PubMed PMID: 27606431.

Dr. Salsbury’s MyBibliography page; not always updated.