English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

We present a new method that combines alchemical transformation with physicalpathway to accurately and efficiently compute the absolute binding free energyof receptor-ligand complex. Currently, the double decoupling method (DDM) andthe potential of mean force approach (PMF) methods are widely used to computethe absolute binding free energy of biomolecules. The DDM relies onalchemically decoupling the ligand from its environments, which can becomputationally challenging for large ligands and charged ligands because ofthe large magnitude of the decoupling free energies involved. On the otherhand, the PMF approach uses physical pathway to extract the ligand out of thebinding site, thus avoids the alchemical decoupling of the ligand. However, thePMF method has its own drawback because of the reliance on a ligandbinding/unbinding pathway free of steric obstruction from the receptor atoms.Therefore, in the presence of deeply buried ligand functional groups theconvergence of the PMF calculation can be very slow leading to large errors inthe computed binding free energy. Here we develop a new method called AlchemPMFby combining alchemical transformation with physical pathway to overcome themajor drawback in the PMF method. We have tested the new approach on thebinding of a charged ligand to an allosteric site on HIV-1 Integrase. After 20ns of simulation per umbrella sampling window, the new method yields absolutebinding free energies within ~1 kcal/mol from the experimental result, whereasthe standard PMF approach and the DDM calculations result in errors of ~5kcal/mol and > 2 kcal/mol, respectively. Furthermore, the binding free energycomputed using the new method is associated with smaller statistical errorcompared with those obtained from the existing methods.

Combining Alchemical Transformation with Physical Pathway to Accurately Compute Absolute Binding Free Energy