Minimum energy path methods and reactivity for enzyme reaction mechanisms: a perspective

Abstract In this perspective article, we discuss the link between minimum energy paths and activation parameters for reactions on complex potential energy surfaces involving many possible local minima, as are typically found for enzyme-substrate complexes. Such systems are frequently tackled with hybrid QM/MM methods in order to characterize reactivity. The link between local energy barriers along a minimum energy path, the so-called exponential average of such local energy barriers, and multiconformational transition state theory is discussed. Also, it is shown that in case of positive skewness of the distribution of barrier heights across sets of minimum energy paths, exponential averaging converges relatively quickly with the number of paths used.