Computation of temperature-dependent dissociation rates of metastable protein–ligand complexes

ABSTRACT

Molecular simulations are often used to analyse the stability of protein–ligand complexes. The stability can be characterised by exit rates or using the exit time approach, i.e. by computing the expected holding time of the complex before its dissociation. However determining exit rates by straightforward molecular dynamics methods can be challenging for stochastic processes in which the exit event occurs very rarely. Finding a low variance procedure for collecting rare event statistics is still an open problem. In this work we discuss a novel method for computing exit rates which uses results of Robust Perron Cluster Analysis (PCCA+). This clustering method gives the possibility to define a fuzzy set by a membership function, which provides additional information of the kind ‘the process is being about to leave the set’. Thus, the derived approach is not based on the exit event occurrence and, therefore, is also applicable in case of rare events. The novel method can be used to analyse the temperature effect of protein–ligand systems through the differences in exit rates, and, thus, open up new drug design strategies and therapeutic applications.

KEYWORDS:

• Brownian dynamics
• exit rates
• holding probability
• membership function
• fuzzy set

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The work has partially been financed by the MSO4SC ‘(Mathematical Modelling, Simulation and Optimization for Societal Challenges with Scientific Computing)’.