A metadynamics perspective on the reduction mechanism of the Pt(IV) asplatin prodrug

Enhanced sampling molecular dynamics has been used to model the reduction mechanism of the antitumoral Asplatin Pt(IV) complex, c,c,t-[PtCl2(NH3)2(OH)(aspirin)] in the presence of l-ascorbic acid as reducing agent. In order to overcome the timescale problem, characteristic of many chemical reactions, we enhanced the sampling of the free energy landscape using Metadynamics. To achieve such a goal, the selection of adequate collective variables is crucial for the application of the method. Recently, a new method called Multi-Class Harmonic Linear Discriminant Analysis (MC-HLDA) has been proposed as a tool for constructing collective variables (CVs) for complex chemical processes. The method reduces the dimensionality of the variable space by generating appropriate linear combinations of several relevant chemical descriptors. The aim of this work is to assess the ability and performance of this method in describing the fundamental features of complex chemical reactions such as the Asplatin reduction mechanism in a compact, simple, and physically transparent manner. © 2019 Wiley Periodicals, Inc.