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Integrated Strategies to Elucidate Molecular Recognition

I. Elucidating Molecular Recognition: Parallel MD Simulations

II. Integrating and Digesting Data: Machine Learning

 

I. Elucidating Molecular Recognition: Parallel MD Simulations

Molecular recognition is inherently a dynamic event, as biomolecules sample an ensemble of conformations around their native states. Molecular dynamics (MD) simulations enable assessing this flexibility for protein-ligand complexes. In the past decade the Schiffer lab has developed a strategy of parallel Molecular Dynamics simulations we define as pMD to collectively analyze a series of MD simulations of similar yet distinct molecular complexes to decipher conformational and dynamic differences responsible for changes in molecular recognition. We perform pMD simulations on complexes with varying protein sequence and ligand identity to unravel structural and dynamic properties that underlie coupled changes in molecular recognition.

We have applied this pMD strategy to protein-ligand complexes for series of natural substrates, inhibitors, and protease mutations. Combined with experimental data on strength of binding, we determine which physical properties or molecular interactions are key to molecular recognition for a given system. These changes dictate not only the interdependency of molecular recognition or specificity but also inform inhibitor design. Using this approach we are addressing shortcomings in traditional structure based drug design (SBDD), by incorporating into drug design:

  • Dynamics (flexibility) of protein–ligand complex
  • Impact of mutations remote from the active site
  • Impact of coupled changes within a ligand
  • Interdependency between sub-sites (or binding grooves) within the active site


Manuscript Highlights



Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease.

Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease.
Leidner F, Kurt Yilmaz N, Paulsen J, Muller YA, Schiffer CA.
J Chem Theory Comput. 2018 May 8;14(5):2784-2796. doi: 10.1021/acs.jctc.8b00097. Epub 2018 Apr 18.



 Interdependence of Inhibitor Recognition in HIV-1 Protease.

Interdependence of Inhibitor Recognition in HIV-1 Protease.
Paulsen JL, Leidner F, Ragland DA, Kurt Yilmaz N, Schiffer CA.
J Chem Theory Comput. 2017 May 9;13(5):2300-2309. doi: 10.1021/acs.jctc.6b01262. Epub 2017 Apr 11.



Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease.

Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease.
Ragland DA, Nalivaika EA, Nalam MN, Prachanronarong KL, Cao H, Bandaranayake RM, Cai Y, Kurt-Yilmaz N, Schiffer CA.
J Am Chem Soc. 2014 Aug 27;136(34):11956-63. doi: 10.1021/ja504096m. Epub 2014 Aug 18.



Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease.

Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease.
Mittal S, Cai Y, Nalam MN, Bolon DN, Schiffer CA.
J Am Chem Soc. 2012 Mar 7;134(9):4163-8. doi: 10.1021/ja2095766. Epub 2012 Feb 28.


II. Integrating and Digesting Data: Machine Learning

While we mainly use molecular information derived from pMD simulations, this approach can also incorporate experimental and computational data from various techniques. Integrating these input data, we construct physical "fingerprints" of protein–ligand complexes and use machine learning to extract predictors of molecular recognition and deduce key specific alterations. 

Integrating and Digesting Data: Machine Learning

 


Manuscript Highlights



Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.

Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.
Ragland DA, Whitfield TW, Lee SK, Swanstrom R, Zeldovich KB, Kurt-Yilmaz N, Schiffer CA
J Chem Theory Comput. 2017 Nov 14;13(11):5671-5682. doi: 10.1021/acs.jctc.7b00601. Epub 2017 Oct 9.



 Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease

Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.
Özen A, Lin KH, Kurt Yilmaz N, Schiffer CA.
Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):15993-8. doi: 10.1073/pnas.1414063111. Epub 2014 Oct 29.

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