Non-specific electrostatics is crucial for structure and stability; recently, it has been argued that psychrophilic proteins may also utilize specific electrostatic interactions. Do psychrophilic proteins increase the number of salt bridges for cold adaptation? Are there any changes that occur in their sequence, which helps them to adapt in an extreme environment? Do intra-protein interactions affect their stability? Is there any special type of intra-protein interaction present in psychrophilic protein structure? This study will give all those answers. Sequences (n ~ 100) and structures of psychrophilic isocitrate dehydrogenase and mesophilic isocitrate dehydrogenase extracted from databases. Sequences had been analyzed in BLOCK and non-BLOCK format. The sequences of psychrophiles and mesophiles create two separate clades. The number of charged and uncharged polar residues is very much high in psychrophilic proteins. The formation of long network aromatic–aromatic interactions and network aromatic–sulfur interactions are very crucial for psychrophilic protein stability. Identification of these types of interactions is also a novelty of this study. Favorable mutation of charged residues with high-energy contributions affects the protein stability. This study will help in protein engineering.
Environmental features are vital determinants for the operation of physiological activity in living organisms. Organisms living in very extreme cold temperatures are known as psychrophiles. They live in freezing temperatures ranges 18 to − 20 °C, as in the case of growing at the surface of the ice shelf or Antarctic sea-water. To grow and live in such situations, these organisms have developed various cellular component modifications, most of their enzymes [1,2,3,4]. These species have to reimburse for reducing chemical reaction rates immanent to low temperatures  Psychrophiles or psychrotrophic bacteria usually construct cold-adapted enzymes that are beneficial in maintaining adequate metabolic activity at these extreme temperatures . The higher pliability of psychrophilic enzymes has also been hypothesized to permit better assist the substrates and to go through fast configuration changes essential to catalysis at little energy cost .
Isocitrate dehydrogenase is an essential enzyme in the citric acid cycle, which performs catalyzation on oxidative NAD(P)+-dependent dehydrogenation and decarboxylation of isocitrate to α-ketoglutarate and CO2. The active site of isocitrate dehydrogenase binds the NAD + or NADP + molecule and a Ca2+ or Mg2+ . This metal ion seems to be crucial for catalysis. Bacterial isocitrate dehydrogenase uses phosphorylation for regulation . Isocitrate dehydrogenase has a censorious metabolic purpose and consequently is found in organisms from every domain of life. This enzyme has been widely studied both kinetically and structurally from psychrophilic and mesophilic organisms. Researchers were also found that two structurally different isocitrate dehydrogenases form a single psychrophilic organism named Colwellia psychrerythraea . Monomeric isocitrate dehydrogenases from Colwellia maris, a psychrophilic bacteria, show how site directed mutagenesis helps to increase its catalytic activity . One dimeric unit (IDH-I) from isocitrate dehydrogenase of Colwellia psychrerythraea shows its important role in growth of this bacterium and also suggest the monomeric unit (IDH-I) of this bacterium important for psychrophilic properties . Increasing catalytic activity of isocitrate dehydrogenase from psychrophilic bacteria also helps to maintain stability in such adverse condition .
Isocitrate dehydrogenase is primarily utilized in the food industry as a food acidulant, and because of being a chiral molecule. Isocitrate dehydrogenase is also applied in the pharmaceutical industry and as an essential raw material for the creating of expensive chemicals .
Salt bridge, a non-covalent, electrostatic interaction, plays a crucial role in protein stability . Proteins that found in extreme temperature [15,16,17], pH [18, 19], and high salt [20, 21] concentrations stabilised by salt bridges. The oppositely charged residues of protein that are sufficiently close to each other, participate in this interaction. Salt bridges are generally two types, isolated and network. The numbers of salt bridges are usually high in extremophiles .
Aromatic-aromatic interactions also play significant role in extremophiles protein stabilisation [23,24,25]. In these interactions, the centers of the aromatic rings of the two participating residues dissociated by a distance between 4.5 and 7 Å. Phe, Tyr, and Trp are participating in this interaction. Generally, two aromatic residues interact with each other has been previously reported on some enzymes .
Materials and methods
A detailed analysis of sequences and structures of psychrophilic bacterial isocitrate dehydrogenase was performed in reference to mesophilic proteins. A total (n ≥ 100) bacterial isocitrate dehydrogenase sequences were retrieved from the UniProt  database. The high-resolution crystal structures of isocitrate dehydrogenase were retrieved from the RCSB protein database (PDB) .
Physicochemical and evolutionary properties
All sequences were subject to multiple sequence alignment which was done with the help of CLUSTAL Omega . Both block and non-block formats of the sequence were analyzed. Block of aligning protein sequences was prepared by Block Maker . Non-block and block both formats were interpreted by Protparam [31, 32] and ProtScale  for calculation of physicochemical properties like amino acid composition, Kyte–Doolittle hydrophobic scale , and Grantham polarity . Mean relative abundance (MRA) was calculated from the mean value of psychrophilic bacterial isocitrate dehydrogenase relative to mesophilic bacterial isocitrate dehydrogenase to compare the data. The phylogenetic tree was constructed by Figtree v1.3.1 software 
Analysis of crystal structure
Psychrophilic isocitrate dehydrogenase from Desulfotalea psychrophila (2UXR) and mesophilic isocitrate dehydrogenase from Escherichia coli (4AJA) were extracted from the RCSB PDB for structural analysis. All structures were minimized for 1000 steps using UCSF Chimera . Secondary structures were analyzed by CFSSP server  to calculate the amino acid propensity in coil, helix, turn, and sheet. Mutational effects were calculated by several online servers [39,40,41]. Free desolvation energy was calculated by ProWaVE server . All intra-protein interactions were calculated by PIC server  and Arpeggio server .
Results and discussion
Charged residues have great effect on psychrophilic sequences
Protein sequences are mainly compared by amino acid compositions; because it helps to find the mutation and evolution between them . Amino acid compositions were analyzed by non-block format of sequences.
Results indicate that the high number of polar residues, i.e., both charged polar (acidic and basic) and uncharged polar residue (except E, R, N, and Q), are present in psychrophilic sequences (Fig. 1a). On the other hand, mainly non-polar amino acids are higher in mesophilic homolog. Kyte–Doolittle hydrophobicity for isocitrate dehydrogenase indicates that the psychrophilic isocitrate dehydrogenase is more hydrophilic in nature (Fig. 1b). That means it can easily interact with water . Hydrophilic membranes are generally originated to increase attractive interactions between water and the amino acid residues of membrane such as hydrogen bonding, dipole–dipole interactions, and ion–dipole interaction . Water–protein interactions also increase structural conformations and stability of protein . Grantham polarity indicates that the polarity of psychrophiles is higher than mesophiles (Fig. 1c). Higher amount of polarity also attracts aqueous solvent for better interaction and helps to increase their folding . Those regions showed marked differences in Kyte–Doolittle and Grantham plots were traced by MSA and result showed that those regions are highly conserved by polar residues in psychrophiles. Phylogenetic tree of those sequences of isocitrate dehydrogenase clearly forms two different clades in two different polls showing their orthologous nature (Fig. 1d).
Highly conserved region has been found in psychrophilic isocitrate dehydrogenase (Fig. 2). Those regions are highly occupied by charged residues, which indicate that charged residues have a significant role in psychrophilic protein evolution.
Amino acids propensity in secondary structure
The secondary structures of proteins are divided into coil, helix, sheet, and turn. Helix propensities can make equivalent energetic contributions in both peptides and proteins . It is also reported that helix has a role in protein stabilisation .
Both protein structures contain mostly their residues in helix. Psychrophilic contains 47% residues and mesophilic protein contains 56% residues in helix of their sequences. However, Desulfotalea psychrophila (2UXR) contains high number of residues in the sheet also (44%). Uncharged and charged polar residues are high in helix of 2UXR (21.57% and 35.26%) than 4AJA (20.17% and 32.61%) (Table 1). However, the hydrophobic residues at helix are high in case of Mesophilic protein (47.21%) than psychrophilic protein (43.15%). Charged residues are remarkably show higher abundance in coil of psychrophilic protein (58.33%), but uncharged polar (29.82%) and hydrophobic residues (50.87%) show higher abundance in coil of mesophilic protein. Sheet contains high number of charged and uncharged polar residues in psychrophilic protein (18.33% and 38.33%). However, turn of mesophilic protein contains high number of charged (32.35%) and hydrophobic residues (55.88%). Although, hydrophobic residues of the psychrophilic protein are only high at the turn (52.63%) between all types of secondary structure. Increased numbers of polar residues increase its polarity, helping in protein stabilisation .
Evolving of long network aromatic–aromatic interactions
It is reported that two residues are involved in the formation of aromatic–aromatic [52,53,54]. But here, we have divided this aromatic–aromatic interactions into two divisions; isolated aromatic–aromatic interactions and network aromatic–aromatic interactions.
Although the lengths of both proteins are almost equal, but the numbers of aromatic–aromatic interactions are very much higher in psychrophiles than mesophiles (Table 2). Psychrophiles possess 25 pairs of interactions where 7 act as isolated and rest of pairs forms 2 network interactions. Mesophiles have only isolated pairs (6) and no network aromatic–aromatic interactions. The formation of a very long aromatic–aromatic interaction is first reported here where 11 aromatic residues are participated and form the complex network aromatic–aromatic interactions (Fig. 3). Residue number Phe194 shows enormous effect on stability. When we mutated this residue by other amino acids, it shows destabilisation (Table 3) in every amino acid (except Cys). Therefore, this network aromatic–aromatic interaction might affect psychrophilic protein stability.
Evolving of long network aromatic–sulfur interactions
Interactions between an aromatic and sulfur containing amino acid can stabilise a protein [55,56,57]. Here, we also divided into two groups, isolated and network aromatic–sulfur interactions or pi–sulfur interactions.
The numbers of aromatic–sulfur interactions or pi–sulfur interactions are high in psychrophilic isocitrate dehydrogenase than mesophilic isocitrate dehydrogenase (Table 4). Psychrophilic isocitrate dehydrogenase (2UXR) contains three isolated and two network aromatic–sulfur interactions (Fig. 4), whereas mesophilic isocitrate dehydrogenase (4AJA) contains seven isolated aromatic–sulfur interactions. No network aromatic–sulfur interactions were found in mesophilic isocitrate dehydrogenase. Therefore, those network aromatic–sulfur interactions might play crucial role in psychrophilic isocitrate dehydrogenase stabilisation for extremely cold temperatures.
Effect of other intra-protein interactions
Free solvation energy is a thermodynamic factor that regulates protein solvation or the nature of denaturation . By this property, we can calculate how fast proteins simply denature. The active site of proteins can supply better solvation energy than its surrounding bulk water. The total solvation free energy is coming from two factors: (i) the interaction between the enzyme charges and the charged group; (ii) the interplay between the induced dipoles and the charged group of enzyme . Solvation free energy can also help in protein folding . Previous analysis of the thermodynamics of protein stability discloses universal leaning for proteins that denature at higher temperatures to have higher free energies which provide maximal stability . Increasing of solvation free energy was also reported in some others psychrophilic protein due to increasing discloser of hydrophobic residues at surface which reacts with solvent . Free solvation energy high in psychrophilic isocitrate dehydrogenase than mesophilic isocitrate dehydrogenase which indicates the psychrophilic protein not smoothly denature in exposure with solvent (Table 5).
Salt bridges are also important factors that help in extremophiles’ stabilisation. The numbers of isolated salt bridges are higher in psychrophilic isocitrate dehydrogenase than mesophilic isocitrate dehydrogenase. Those salt bridges might affect psychrophilic protein stability. However, the number of network salt bridges is high in mesophilic isocitrate dehydrogenase. Carbonyl interactions also play a crucial role in psychrophilic protein stability as they show higher number than mesophiles. Carbonyl interactions also have an effect on protein stabilisation .
Favorable mutation by charged residues
Mutation on amino acid residues helps in extremophilic protein stabilisation. MSA of psychrophilic and mesophilic isocitrate dehydrogenase shows the appearance of charged residues in some position in psychrophilic isocitrate dehydrogenase (Fig. 5). Therefore, we check their mutational effect and also calculate their energy contributions.
We have identified 11 positions where mesophilic residues mutated by a charged residue and the mutation goes favorable for psychrophiles (Table 6). That means, introduction of charged residue in their sequences has a great effect on their stability. Tyr134Lys shows highest contribution after favorable mutation contributes − 6.33 kcal/mol energies on protein stability. Psychrophiles specially design their sequence with the help of some specific single amino acid mutations to stabilise themselves in cold environment. These types of specially designed psychrophilic enzymes are also reported in the previous studies.
Evolutions play a crucial role in psychrophilic protein stability in such extremely freezing temperatures. This evolution is mainly contributed by charged amino acids, which affect the sequence properties and affect the structural properties. Formation of massive long aromatic–aromatic interaction and network aromatic–sulfur interaction are the novel foundation of this study. Such types of aromatic–aromatic interaction are never seen before. Those interactions highly affect protein stability. Ultimately, the mutation study shows how charged residues help in protein stabilisation with enormous energy contribution. Finally, the study seems to have potential applications in industrial purposes and protein engineering.
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Mitra, D., Das Mohapatra, P.K. Cold adaptation strategy of psychrophilic bacteria: an in-silico analysis of isocitrate dehydrogenase. Syst Microbiol and Biomanuf 1, 483–493 (2021). https://doi.org/10.1007/s43393-021-00041-z
- Cold adaptation
- Aromatic–aromatic interactions
- Aromatic–sulfur interactions
- Non-covalent interactions