Adaptive Multilevel Splitting Method for Molecular Dynamics Calculation of Benzamidine-Trypsin Dissociation Time

Abstract

Adaptive Multilevel Summation (AMS) is a rare event sampling method that requires minimal parameter tuning and that allows unbiased sampling of transition pathways of a given rare event. Previous simulation studies have verified the efficiency and accuracy of AMS in the calculation of transition times for simple systems in both Monte Carlo and molecular dynamics (MD) simulations. Now, AMS is applied for the first time to a MD simulation of protein-ligand dissociation, representing a leap in complexity from the previous test cases. Of interest is the dissociation rate, which is typically too low to be accessible to conventional MD. The present study joins other recent efforts to develop advanced sampling techniques in MD to calculate dissociation rates, which are gaining importance in the pharmaceutical field as indicators of drug efficacy. The system investigated here, benzamidine bound to trypsin, is an example common to many of these efforts. The AMS estimate of the dissociation rate was found to be (2.6 ± 2.4) × 102 s−1, which compares well with the experimental value.

Analysis of the adaptive multilevel splitting method on the isomerization of alanine dipeptide

“…The consistency of (17) has already been tested on various systems in previous works. [9,10] In this article, we numerically investigate the quality of formula (17) using the estimate of p obtained with AMS starting from μ QSD . Note that the sampling of μ QSD as well as E T loop À Á can be obtained with short direct simulations whereas AMS is used to get both p and E T reac ð Þ.…”

“…In particular, the AMS method was already efficiently applied to a large-scale system to calculate unbinding time. [9] Let us emphasize that the AMS algorithm can be used not only to estimate the probability of a rare event but also to simulate the associated rare events (typically, the ensemble of reactive trajectories in the context of molecular dynamics). This allows us to study the possible transition mechanisms that are often more than one and to estimate the committor function, for example.…”

“…Compared to previous publications on AMS, [9,10] we provide in this article a full description of the correct way to implement the algorithm in a discrete in time setting. The reader will find this description in the Methods' section, as well as a brief discussion of some important properties of the method and the way to obtain the transition time using AMS.…”

Path-sampling strategies for simulating rare events in biomolecular systems

“…In addition, two studies have demonstrated the power of path sampling strategies in generating atomistic pathways for protein-ligand unbinding processes and the corresponding k off values, which are of great interest for drug design efforts. These studies involve a) the application of the WE approach to the FK506 binding protein and several low-affinity, small-molecule inhibitors, which unbind on timescales up to tens of ns, resulting in the first analysis of ligand-exit distributions [*64], and b) the application of the AMS approach to trypsin and the benzamidine inhibitor, which unbinds on the ms timescale [65]. In addition, it has been demonstrated that experimental k on values can be efficiently reproduced for various protein-ligand systems using milestoning as part of an atomistic MD/Brownian Dynamics approach [66].…”

Accelerating Dissociative Events in Molecular Dynamics Simulations by Selective Potential Scaling

“…The use of specialized computer hardware coupled with optimized software have significantly extend the timescales that are accessible during MD simulations (6)(7)(8)(9)(10)(11), but access to such computers is still limited. Fortunately, many enhanced sampling algorithms have been developed that can be used to accelerate dissociative processes in multi-component biomolecular systems during simulations (12)(13)(14)(15)(16)(17)(18).…”