Total Free Energy Analysis of Fully Hydrated Proteins

Jas Kalayan, Arghya Chakravorty, James Warwicker, Richard Henchman

Research output: Contribution to journalArticlepeer-review


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 destabilised relative to singly solvated amino acids, while trends for other residues are less clear-cut. Almost all residues lose intra-residue 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 strands and turns, and least stable around helices. An interesting asymmetry observed is that cationic residues stabilise a residue when bonded to its N-terminal side but destabilise it when on the C-terminal side, with a weaker reversed trend for anionic residues.
Original languageEnglish
JournalProteins: Structure, Function and Bioinformatics
Publication statusAccepted/In press - 9 Aug 2022


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