Noncovalent interactions (NIs) are present in the properties and functions of all matter, from solid state to soft materials. These interactions can range from a few kcal/mol to several hundreds or even thousands of kcal/mol. Ubiquitous to all molecules is the presence of dispersion interactions, which is a force allowing geckos to stick onto walls. However, dispersionremains challenging to intuitively understand and accurately predict. In this thesis, I investigate the dissociation of Leishmania major peroxidase using atomistic molecular dynamics (MD), revisit the current understanding of many-body perturbation theory for NIs, introduce an exact constraint known as the dispersion size-consistency along with its importance for electronic structure methods, and apply that knowledge to understand the novel face-on halogen-π interaction between the lissoclimide family and eukaryotic 80S ribosome.
In chapter 2, I investigate the dissociation of Leishmania major peroxidase from MD and contribute to the understanding of the interactions between heme proteins and its electron-transferring redox partner. Peroxidases function to catalyze the reduction of peroxide into water and molecular oxygen. This allows parasites such as Leishmania major to evade reactive oxygen species (ROS) from the host’s defenses. Leishmania major peroxidase (LmP) and cytochrome c (Cytc) form a complex that mediates interprotein electron transfer (ET) and reduces ROS. Such a complex must navigate between fast turnover and tight binding. A previous Brownian dynamics study showed that LmCytc associates with the LmP by first interacting with helix A of LmP and then moving toward the ET site. Critical to this association is the intermolecular Arg-Asp ion pair at the center of the interface. In anticipation, the dissociation process is the reverse by breaking the Asp-Arg ion pair and follow by the movement towards LmP helix A. To test this, I performed multiple MD simulations along with in silico mutation of the LmP Asp211 to Ala211 and observed the dissociation process consistent with the experiment.
In chapters 3 and 4, I revisit the many-body perturbation (MBPT) for NIs due to alarmingly large binding energy errors obtained from MBPT. Currently, NIs have traditionally been understood as “weak” relative to covalent bonds on the order of several magnitudes. Due to this weakness, MBPT has been expected to accurately model NIs. This was observed with small complexes from the S22 testset. I reassess the performance of the second-order Møller-Plesset MBPT (MP2) and compare the results to spin-scaled MP2, dispersion-corrected semilocal density functional approximations (DFAs), and post-Kohn–Sham random phase approximation (RPA). These methods is benchmarked against the S66, L7, and S30L testsets for predicted binding energies. All binding energies are extrapolated to the complete basis set limit, corrected for basis set superposition errors, and compared to the reference results of the domain-based local pair-natural orbital coupled-cluster (DLPNO-CCSD(T)) or better quality. The results reveal that MP2 significantly overestimates the binding energies. In some cases, the MP2 relative errors are over 100%. Spin-scaled MP2, while an improvement, still inherits the limitations of MP2. RPA and dispersion-corrected DFAs have similar performance ranging between 5% to 10% errors. A regression analysis shows that MP2 binding energy errors grew with the system size by at rate of ∼ 0.1% per valence electron, whereasRPA and dispersion-corrected DFA errors remain constant.
To understand the errors, I develop an asymptotic adiabatic connection symmetry-adapted perturbation theory (AC-SAPT). The theory considers a supersystem in terms of the non-overlapping monomers at full coupling whose ground-state density is constrained to the ground-state of the supersystem. Using the fluctuation-dissipation theorem, a nonperturbative “screened second-order” expression for the dispersion energy in terms of the monomer basis is obtained. AC-SAPT expansion of the interaction energy reveals that the source of binding energy errors come from missing or an incomplete “electrodynamic” screening of the Coulomb interaction due to induced particle-hole pairs between electrons in different monomers. MP2 and higher-ordered perturbation theories lack this property leading to a divergent series within the AC-SAPT framework, whereas RPA converges. Furthermore, extension of the AC-SAPT framework to the thermodynamic limit establishes the dispersion size-consistency, which states that the total dispersion energy of an N -monomer system is independent of any partitioning into subsystems. MBPT is found to violate this condition and RPA does not. This is due to the additive separability of the dispersion energy results from multiplicative separability of the generalized screening factor defined as the inverse generalized dielectric function. Based on the computational and theoretical results, MBPT may not be qualitatively and quantitatively adequate for prediction of NIs. Nonperturbative methods such as RPA or coupled cluster methods should be used.
In chapter 5, I collaborated with the Vanderwall Lab to understand the novel face-on halogen-π interaction between the lissoclimide family and eukaryotic 80S ribosome. The model is based on the structure-activity relationship (SAR) of the lissoclimide family inhibition of protein synthesis obtained from the X-ray co-crystal structure of the 80S ribosome and chlorolissoclimide. I took advantage of the SAR and instead of modeling the ∼ 400, 000 atoms from the crystal structure, the region where the chlorolissoclimide binds is studied instead. The system includes the lissoclimide family, two guanine nucleobases, and the phospahte backbone. This becomes a manageable 122 atoms system for electronic structure methods. The remaining protein environment is approximated using the implicit conductor-like solvation model. I verify the model by correlating the experimental half-maximum inhibitor concentration (IC 50 ) and RPA predicted binding energies between the lissoclimide derivatives and the eukaryotic 80S ribosome. The relationship reveals a negative correlation consistent with the anticipation that stronger binding leads to a more potent inhibitor. Based on these results, I proposed additional inhibitors and contributed to an expanded SAR knowledge of the lissoclimide family inhibition.
