Water follows polar and nonpolar protein surface domains

Abstract

The conformation of water around proteins is of paramount importance, as it determines protein interactions. Although the average water properties around the surface of proteins have been provided experimentally and computationally, protein surfaces are highly heterogeneous. Therefore, it is crucial to determine the correlations of water to the local distributions of polar and nonpolar protein surface domains to understand functions such as aggregation, mutations, and delivery. By using atomistic simulations, we investigate the orientation and dynamics of water molecules next to 4 types of protein surface domains: negatively charged, positively charged, and charge-neutral polar and nonpolar amino acids. The negatively charged amino acids orient around 98% of the neighboring water dipoles toward the protein surface, and such correlation persists up to around 16 Å from the protein surface. The positively charged amino acids orient around 94% of the nearest water dipoles against the protein surface, and the correlation persists up to around 12 Å. The charge-neutral polar and nonpolar amino acids are also orienting the water neighbors in a quantitatively weaker manner. A similar trend was observed in the residence time of the nearest water neighbors. These findings hold true for 3 technically important enzymes (PETase, cytochrome P450, and organophosphorus hydrolase). Our results demonstrate that the water−amino acid degree of correlation follows the same trend as the amino acid contribution in proteins solubility, namely, the negatively charged amino acids are the most beneficial for protein solubility, then the positively charged amino acids, and finally the charge-neutral amino acids.

Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites

“… 30 A simple estimate using a dielectric permittivity reduction from 80 to 8 up to ∼1 nm from the protein surface changes the Coulomb energy ( E ) over thermal energy ( k B T ) between two elementary charges ( e ) separated by a distance d [ E / k B T = e ( 2 )/(4 r d )/ k B T = l B / d ] from 0.7 to 7 when d = 1 nm, also strongly reducing the debye length from the value in water (∼1 nm in bulk water with 150 mM of NaCl). An increase in protein’s absolute net charge, which drives stronger interfacial correlations, 24 therefore, explains the long-range impact of the polybasic cleavage sites on the RBD–ACE2 binding given the fact that the SARS-CoV-2 spike protein trimer and ACE2 are both highly negatively charged with a net charge of −21 e and −28 e , respectively.…”

“…The hydrophobic leucine (Leu) residue was introduced to decrease the hydration, as a test simulation on a tetrapeptide EEEE showed that EEEE became quickly dissolved (within 10 ns) owing to the high hydration of the negatively charged amino acids. 24 − 26 …”

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

“…All the covalent bonds were constrained, which supported an integration time step of 2.5 fs. These parameters were recommended for the accurate reproduction of the original CHARMM simulation on lipid membrane system 38 and were verified in simulations on proteins 20,39,40 and lipid membranes 41 . The production simulation lasted 100 ns.…”

“…Moreover, the substitution of positively charged arginine with negatively charged glutamic acid increases protein hydration (Table S2), which is consistent with the fact that negatively charged amino acids exhibit stronger hydration than positively charged ones. [20][21][22] Further analysis of the intermolecular hydrogen bonds between the RBD and ACE2 demonstrated a similar influence of the mutants (Figure 2F). For the WT spike protein, there exist 8 ± 1 hydrogen bonds between the RBD and ACE2.…”

“…The hydrophobic leucine (Leu) residue was introduced to decrease the hydration, as a test simulation on a tetrapeptide EEEE showed that EEEE became quickly dissolved (within 10 ns) owing to the high hydration of the negatively charged amino acids. [20][21][22] Potential energy and number of hydrogen bonds between the RBD and ACE2. In (C), the averages and standard deviations are from five parallel runs (Figure 4).…”