Solvation in simulated annealing and high-temperature molecular dynamics of proteins: A restrained water droplet model

Abstract

ABSTRACT:The use of explicit water molecules in simulations of protein systems in solution at high temperatures (e.g., in simulated annealing protocols) is complicated by the temperature-dependent changes in the physical properties of water. We propose a new protocol for such simulations based on a solvation model in which a spherical harmonic restraint is applied to a water shell surrounding the primary solvent sphere containing the polypeptide. The performance of different force constants, applied in water shells of different widths, was tested in simulations at temperatures ranging from 300 to 500 K. The best results were obtained when small force constants (0.0007-0.002 kcal/mol Å 2 ) were applied to 5-Å water shells surrounding the primary water sphere constructed to accommodate the solute and water at the appropriate density. With an atom-based 14-Å cut-off this solvation model reproduces structural and dynamic properties of water in the range of temperatures tested here. Thus, the internal pressure is very well maintained during cooling in simulated annealing protocols, and the small force constants eliminate the potential artifacts of the surface effects and prevent the water molecules from evaporating in simulations at high temperature. The restrained water droplet model described here is computationally more economical than periodic boundary conditions (PBC) and is preferable to the PBC method in which the size of the box has to be adjusted to maintain the experimental density if simulations are performed at different temperatures. Its application is illustrated in the study of the extracellular domain of the receptor protein for the gonadotropin releasing hormone (GnRH). This receptor belongs to the family of seven transmembrane domain proteins involved in signal transduction from the extracellular environment into the cell. The extracellular loops (ECLs) connecting the seven transmembrane (TM) domains are exposed to aqueous solvent and play a key role in binding GnRH to its receptor. The solvation model was used in a successful simulated * Dedicated to Prof. Michael Zerner on his 60th birthday. CCC 0020-7608 / 00 / 010174-13 SIMULATED ANNEALING AND HIGH-TEMPERATURE MOLECULAR DYNAMICS OF PROTEINSannealing protocol that explored the conformational space of the interacting ECLs. We show that the resulting secondary structure of ECL 3 is supported by experimental data and depends on hydrophobic interactions that appear only in an appropriate representation of the solvent but cannot be obtained from the commonly used simulations in vacuum with the solvent modeled solely through a dielectric constant.

Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP2 -containing membranes

“…The latter restraining potential was necessary only in rare cases and only at the highest temperatures considered (the restraint not active >95% of the time at 500 K), showing that the water droplet was large enough to accommodate the peptide as it underwent conformational changes during REMD. Importantly, we verified that MD simulations performed with the above set of restrains resulted in water densities that were in good agreement with those established from experiments for the entire [290–500]K temperature range (see Supporting Information Fig. S2B).…”

“…To keep the solute in the water phase at all times during the REMD and to maintain proper water density across the simulation box at all temperatures, a combination of several restraining potentials was used: (1) A soft harmonic potential (with k = 0.002 kcal/mole/Å 2 force constant) restrained waters that were at a distance greater than ( R ‐ 5)Å from the water droplet center, R being the radius of the water sphere; (2) A hard harmonic potential (with k = 1 kcal/mole/Å 2 ) was applied to waters at distances ( R + 5)Å or greater from the water droplet center to avoid water evaporation; (3) The center of mass of the solute was restrained to the center of the water drop using k = 1 kcal/mole/Å 2 as a force constant; (4) The solute molecules were restrained to a sphere of radius ( R ‐ 5)Å by applying a harmonic force with k = 0.25 kcal/mole/Å 2 force constant to those solute atoms that were at a distance greater than ( R ‐ 5)Å. The latter restraining potential was necessary only in rare cases and only at the highest temperatures considered (the restraint not active >95% of the time at 500 K), showing that the water droplet was large enough to accommodate the peptide as it underwent conformational changes during REMD.…”

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

“…Hence a reliable GPCR model has to be built to dock the ligand in its binding site that satisfies the results obtained by sitedirected mutagenesis, spectroscopy and other experiments. Loop modeling remains one of the main problems in GPCR protein modeling [185][186][187]. A carefully built receptor-ligand complex model will help to understand the mechanism by which the ligand-receptor complex activates the G-protein and thus can aid in the rational drug design and development.…”

Computation of methodology-independent single-ion solvation properties from molecular simulations. IV. Optimized Lennard-Jones interaction parameter sets for the alkali and halide ions in water

“…The corresponding (additive) corrections may be evaluated using continuum electrostatics (or empirical equations fitted against the results of such calculations 3 ) and analytical models, and must account for 2,3 (A) The deviation of the solvent polarization around the ion relative to the polarization in an ideal Coulombic (CB) system 2, 3, 5-18 and the incomplete or/and inexact interaction of the ion with the polarized solvent, 2,9,13,14,19 a consequence of possible approximations made in the representation of electrostatic interactions during the simulation [e.g., non-Coulombic interactions involving cutoff truncation 20 (CT), possibly along with other functional modifications, as opposed to CB or latticesum (LS) interactions]. (B) The deviation of the solvent polarization around the ion relative to the polarization in an ideal macroscopic system, 2,3,9,12,[15][16][17][18][21][22][23][24][25][26][27] a consequence of the use of a finite (microscopic and possibly periodic) system during the simulation [e.g., finite droplet simulated under fixed boundary conditions [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] (FBC) or computational box simulated under periodic boundary conditions 20,…”