Toward Determining ATPase Mechanism in ABC Transporters: Development of the Reaction Path-Force Matching QM/MM Method.

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are ubiquitous ATP-dependent membrane proteins involved in translocations of a wide variety of substrates across cellular membranes. To understand the chemomechanical coupling mechanism as well as functional asymmetry in these systems, a quantitative description of how ABC transporters hydrolyze ATP is needed. Complementary to experimental approaches, computer simulations based on combined quantum mechanical and molecular mechanical (QM/MM) potentials have provided new insights into the catalytic mechanism in ABC transporters. Quantitatively reliable determination of the free energy requirement for enzymatic ATP hydrolysis, however, requires substantial statistical sampling on QM/MM potential. A case study shows that brute force sampling of ab initio QM/MM (AI/MM) potential energy surfaces is computationally impractical for enzyme simulations of ABC transporters. On the other hand, existing semiempirical QM/MM (SE/MM) methods, although affordable for free energy sampling, are unreliable for studying ATP hydrolysis. To close this gap, a multiscale QM/MM approach named reaction path-force matching (RP-FM) has been developed. In RP-FM, specific reaction parameters for a selected SE method are optimized against AI reference data along reaction paths by employing the force matching technique. The feasibility of the method is demonstrated for a proton transfer reaction in the gas phase and in solution. The RP-FM method may offer a general tool for simulating complex enzyme systems such as ABC transporters.

Replica exchange molecular dynamics simulations of an α/ß-type small acid soluble protein (SASP).

Small acid soluble proteins (SASPs) of α/ß-type play a major role in the resistance of spore DNAs to external assaults. It has been found that α/ß-type SASP exhibits intrinsic disorder on isolation, but it acquires a defined native state upon binding to DNA. This disorder to order transition is not yet understood. Other questions related to the role of the thermodynamics and structure of the individual protein in the complex formation remain elusive. Characterization of the unbound state of α/ß-type SASP in experiments could be a challenging problem because of the heterogeneous nature of the ensemble. Here, computer simulations can help gain more insights into the unbound state of α/ß-type SASP. In the present work, by using replica exchange molecular dynamics (REMD), we simulated an α/ß-type SASP on isolation with an implicit solvent. We found that α/ß-type SASP undergoes a continuous phase transition with a small free energy barrier, a common feature of intrinsically disordered proteins (IDPs). Additionally, we detected the presence of residual α-helical structures at local level and a high degree of plasticity in the chain which can contribute to the fast disorder to order transition by reducing the fly-casting mechanism.

Traveling kinks in cubic nonlinear Ginzburg-Landau equations.

Nonlinear cubic Euler-Lagrange equations of motion in the traveling variable are usually derived from Ginzburg-Landau free energy functionals frequently encountered in several fields of physics. Many authors considered in the past damped versions of such equations, with the damping term added by hand simulating the friction due to the environment. It is known that even in this damped case kink solutions can exist. By means of a factorization method, we provide analytic formulas for several possible kink solutions of such equations of motion in the undriven and constant field driven cases, including the recently introduced Riccati parameter kinks, which were not considered previously in such a context. The latter parameter controls the delay of the switching stage of the kinks. The delay is caused by antikink components that are introduced in the structure of the solution through this parameter.