No abstract

Gleevec (a.k.a., imatinib) is an important anticancer (e.g., chronic myeloid leukemia) chemotherapeutic drug due to its inhibitory interaction with the Abl kinase. Here, we use atomically detailed simulations within the Milestoning framework to study the molecular dissociation mechanism of Gleevec from Abl kinase. We compute the dissociation free energy profile, the mean first passage time for unbinding, and explore the transition state ensemble of conformations. The milestones form a multidimensional network with average connectivity of about 2.93, which is significantly higher than the connectivity for a one-dimensional reaction coordinate. The free energy barrier for Gleevec dissociation is estimated to be ∼10 kcal/mol, and the exit time is ∼55 ms. We examined the transition state conformations using both, the committor and transition function. We show that near the transition state the highly conserved salt bridge K217 and E286 is transiently broken. Together with the calculated free energy profile, these calculations can advance the understanding of the molecular interaction mechanisms between Gleevec and Abl kinase and play a role in future drug design and optimization studies.

Recent molecular modeling methods using Markovian descriptions of conformational states of biomolecular systems have led to powerful analysis frameworks that can accurately describe their complex dynamical behavior. In conjunction with enhanced sampling methods, such as replica exchange molecular dynamics (REMD), these frameworks allow the systematic and accurate extraction of transition probabilities between the corresponding states, in the case of Markov state models, and of statistically-optimized transition rates, in the case of the corresponding coarse master equations. However, applying automatically such methods to large molecular dynamics (MD) simulations, with explicit water molecules, remains limited both by the initial ability to identify good candidates for the underlying Markovian states and by the necessity to do so using good collective variables as reaction coordinates that allow the correct counting of inter-state transitions at various lag times. Here, we show that, in cases when representative molecular conformations can be identified for the corresponding Markovian states, and thus their corresponding collective evolution of atomic positions can be calculated along MD trajectories, one can use them to build a new type of simple collective variable, which can be particularly useful in both the correct state assignment and in the subsequent accurate counting of inter-state transition probabilities. In the case of the ubiquitously used root-mean-square deviation (RMSD) of atomic positions, we introduce the relative RMSD (RelRMSD) measure as a good reaction coordinate candidate. We apply this method to the analysis of REMD trajectories of amyloid-forming diphenylalanine (FF) peptides-a system with important nanotechnology and biomedical applications due to its self-assembling and piezoelectric properties-illustrating the use of RelRMSD in extracting its temperature-dependent intrinsic kinetics, without assumptions on the functional form (e.g., Arrhenius or not) of the underlying conformational transition rates. The RelRMSD analysis enables as well a more objective assessment of the convergence of the REMD simulations. This type of collective variable may be generalized to other observables that could accurately capture conformational differences between the underlying Markov states (e.g., distance RMSD, the fraction of native contacts, etc.).

No abstract

The self-assembling propensity of amyloid peptides such as diphenylalanine (FF) allows them to form ordered, nanoscale structures, with biocompatible properties important for biomedical applications. Moreover, piezoelectric properties allow FF molecules and their aggregates (e.g., FF nanotubes) to be aligned in a controlled way by the application of external electric fields. However, while the behavior of FF nanostructures emerges from the biophysical properties of the monomers, the detailed responses of individual peptides to both temperature and electric fields are not fully understood. Here, we study the temperature-dependent conformational dynamics of FF peptides solvated in explicit water molecules, an environment relevant to biomedical applications, by using an enhanced sampling method, replica exchange molecular dynamics (REMD), in conjunction with applied electric fields. Our simulations highlight and overcome possible artifacts that may occur during the setup of REMD simulations of explicitly solvated peptides in the presence of external electric fields, a problem particularly important in the case of short peptides such as FF. The presence of the external fields could overstabilize certain conformational states in one or more REMD replicas, leading to distortions of the underlying potential energy distributions observed at each temperature. This can be overcome by correcting the REMD initial conditions to include the lower-energy conformations induced by the external field. We show that the converged REMD data can be analyzed using a Markovian description of conformational states and show that a rather complex, 3-state, temperature-dependent conformational dynamics in the absence of electric fields collapses to only one of these states in the presence of the electric fields. These details on the temperature- and electric-field-dependent thermodynamic and kinetic properties of small FF amyloid peptides can be useful in understanding and devising new methods to control their aggregation-prone biophysical properties and, possibly, the structural and biophysical properties of FF molecular nanostructures.