Molecular mechanics simulation of protein-ligand interactions: binding of thyroid hormone analogs to prealbumin

Abstract

We have simulated the interaction of L-thyroxine (l), D-thyroxine (2), and their deamino (3) and decarboxy (4) analogues with the human plasma protein prealbumin by using molecular mechanics calculations. Starting geometries were taken from the high-resolution X-ray structure of prealbumin and difference electron density maps of the prealbumin-thyroxine complex. We model the interactions by using the atoms of the thyroxine analogue and approximately 250 atoms within the binding site of prealbumin, minimizing the total energy with respect to all geometric degrees of freedom. Using the molecular mechanics calculated interaction energies and a simple empirical method to estimate the solvation energy differences of 1-4, we qualitatively reproduce the experimentally observed relative free energies of association of these analogues to prealbumin and offer a structural and energetic model to account for the different binding affinities of analogues 1-4 to the protein.

Derivation of force fields for molecular mechanics and dynamics from ab initio energy surfaces

“…2 constitutes the Discover force field, which is based upon the VFF approach (2)(3)(4)(5)(6)(7)15). Other force fields exist [e.g., MM2 (8), AMBER (16,17,19,21), and CHARMM (18,20)] and mainly vary with respect to the inclusion or omission of cross terms and the degree of anharmonicity of the bonds and bending angles. These analytical force fields are to be distinguished from standard ab initio and vibrational force fields (22-43, 45, 46), sometimes termed GVFF (general valence force field) or GHFF (general harmonic force field).…”

“…Each spring was characterized by a coordinate s (bond, angle, or out-of-plane coordinate) and two parameters, a force constant k and a "strain free" reference value so, Vspring = k(s -so)2. Basically, this simple diagonal form is the force field used in most protein simulations (16)(17)(18)(19)(20)(21). The second force field was equally diagonal but included some anharmonicities in the form of cubic terms for all coordinates tFor this minimization we used as an initial geometry the equilibrium structure calculated with the analytical form (Eq.…”

“…However, the results of these simulations depend critically on the set of potential energy functions (i.e., force field) used. Although a great deal ofeffort has gone into the derivation offorce fields now in use (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), there remain many more organic and biomolecular functional groups for which adequate parameters have yet to be derived. Moreover, even the functional form required to describe molecular energy surfaces is still a subject of research (1).…”

Electrostatic Lock-and-Key Model for the Study of Biological Isosterism: Role of Structural Water in the Binding of Basic Pancreatic Trypsin Inhibitor to ß-Trypsin

“…We have studied these factors in a series of publications [7,20,21,23,25] and formulated some simple prin ciples which govern electrostatic interactions between proteins and their ligands. Though several publications exist in the literature, which report on the quantitative estimation of protein-ligand interaction energies [6,23,27, 32], we feel that qualitative rules are often …”

Computer graphics in real‐time docking with energy calculation and minimization

“…The partial atomic charges and the van der Waals constants were taken from Blaney et a1. 21 Various dielectric models such as E = I(R, -Rd)l, E = 1 and 4, were considered. In the receptor site, we define a box where the ligands and its analogues are more likely to be placed and moved around.…”