Targeting inactive states of protein kinases, specifically and efficiently, has been a goal in drug discovery over the past 30 years. To obtain insights about how and why a specific kinase conformation is addressed as a potential target to an inhibitor, there have been many reports of molecular dynamics simulation studies of the active to inactive conformational transitions. However, determination of a physical pathway or appropriate set of collective variables (CV) between two end states is not trivial. Here we apply the second version of Restraint-Free Energy Perturbation-Release (R-FEP-R-2) to estimate the free energy differences between the kinase active and inactive states [1]. R-FEP-R-2 is a CV- and physical-pathway- independent method that follows an alchemical pathway to close a thermodynamic cycle connecting the desired target states. Our final goal is to estimate the free energy difference of DFG-in (active) to classical DFG-out (inactive) conformation, where the activation loop changes from extended to folded, respectively. First we apply our method to study the DFG-in (active) to DFG-in (inactive) conformational change. The DFG-in (inactive) conformation in this study was initially purposed as an intermediate state in transition pathway from DFG-in to DFG-out [2]. The DFG-in (inactive) has been observed among over ~ 40 sequences up to date. Finally, by comparing the free energy differences between the two end states over various sequences, we will be able to propose potential kinase families as inactive conformations favorably targeted by available type I inhibitors.<br/>

Exploring the free energy landscape of protein kinases using an alchemical pathway; restraint-free energy perturbation-release 2<sup>ed</sup> version (R-FEP-R-2)

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Exploring the free energy landscape of protein kinases using an alchemical pathway; restraint-free energy perturbation-release 2ed version (R-FEP-R-2)

Exploring the free energy landscape of protein kinases using an alchemical pathway; restraint-free energy perturbation-release 2^ed version (R-FEP-R-2)