Total free energy analysis of fully hydrated proteins

Abstract

The total free energy of a hydrated biomolecule and its corresponding decomposition of energy and entropy provides detailed information about regions of thermodynamic stability or instability. The free energies of four hydrated globular proteins with different net charges are calculated from a molecular dynamics simulation, with the energy coming from the system Hamiltonian and entropy using multiscale cell correlation. Water is found to be most stable around anionic residues, intermediate around cationic and polar residues, and least stable near hydrophobic residues, especially when more buried, with stability displaying moderate entropy-enthalpy compensation. Conversely, anionic residues in the proteins are energetically destabilized relative to singly solvated amino acids, while trends for other residues are less clear-cut. Almost all residues lose intraresidue entropy when in the protein, enthalpy changes are negative on average but may be positive or negative, and the resulting overall stability is moderate for some proteins and negligible for others. The free energy of water around single amino acids is found to closely match existing hydrophobicity scales. Regarding the effect of secondary structure, water is slightly more stable around loops, of intermediate stability around β strands and turns, and least stable around helices. An interesting asymmetry observed is that cationic residues stabilize a residue when bonded to its N-terminal side but destabilize it when on the Cterminal side, with a weaker reversed trend for anionic residues.

QSAR modelling, molecular docking, molecular dynamic and ADMET prediction of pyrrolopyrimidine derivatives as novel Bruton’s tyrosine kinase (BTK) inhibitors

“…The AMBER 14( Salomon-Ferrer et al, 2013 ) package with the AMBER force field FF99 ( Spasic et al, 2012 ) was also used to minimize, add counter ions, solvate, equilibrate, and run periodic box, explicit water (TIP4P) MD simulations for the best inhibitors. The protein–ligand-water system data analysis was carried out with the AMBER Tools distribution program ( Kalayan et al, 2023 , Kalayan et al, 2021 ).…”

The biophysics of water in cell biology: perspectives on a keystone for both marine sciences and cancer research

“…Earlier works questioning the thermodynamic explanation for water-protein interactions ( Watterson, 1997 ), and how solid-state physics could help understand the behavior of hydrated proteins ( Teeter et al, 2001 ), found some echo in recent publications. First, free energies analyzed for four hydrated globular proteins differing by their net charges revealed that water was most stable around anionic residues, and least stable near hydrophobic residues ( Kalayan et al, 2023 ). As most biomacromolecules fold into chiral structures for their biological functions, how water molecules rearrange to minimize free energy at interfaces was shown, with achiral water molecules assembling in the first hydration shell of the protein into a chiral supramolecular structure with chirality transferred from the protein ( Yan et al, 2023 ).…”

Energy-entropy multiscale cell correlation method to predict toluene–water log P in the SAMPL9 challenge

“…In EE-MCC the energy is taken from the MD simulations and the entropy is calculated for both solute and solvents over all degrees of freedom at multiple length scales. MCC has been developed for liquids, 29,30,32 solutions, [33][34][35][36] chemical reactions, 37 host-guest systems, 38 and proteins 31,[39][40][41] and offers the advantage of providing a comprehensive breakdown of entropy across all atomic degrees of freedom.…”