Bidirectional path-based non-equilibrium simulations for binding free energy

Abstract

Estimating free energy is a fundamental computational challenge, especially in complex biological systems characterised by numerous degrees of freedom. In this study, we investigate the potential of leveraging non-equilibrium free energy estimators within path-based approaches; this offers an appealing feature of inherent parallelism. Building upon our prior work on protein-ligand binding free energy calculations, we develop its non-equilibrium counterpart. We begin by validating our computational strategy on a simple toy model and then extend our analysis to the well-established trypsin-benzamidine complex, serving as a benchmark system. Subsequently, we apply this method to a more intricate, relevant pharmaceutical system to evaluate the performance of our computational pipeline on this complex system. Our results not only demonstrate the feasibility of this approach but also shed light on potential limitations. Furthermore, we showcase the capabilities of the Jarzynski and Crooks estimators employed in our study.

GRAPHICAL ABSTRACT

Keywords:

• Steered molecular dynamics
• Binding free energy
• Crooks fluctuation theorem
• Jarzynski equality
• Path collective variables

Acknowledgments

A.G. thanks the European project "Molecular Dynamics Data Bank. The European Repository for Biosimulation Data" grant number 101094651 for financial support. We thank the High Performance Computing team at the Data Science and Computation Facility in IIT for computing time on the Franklin platform. We also acknowledge UCSF for the Chimera molecular graphics software suite we used for the graphical abstract.

Data availability statement

MD input files, molecular topologies and codes are available upon request.

Disclosure statement

No potential conflict of interest was reported by the author(s).