Cysteine, a semi-essential amino acid, is found in the active site of a number of vital enzymes of the bacterium Mycobacterium tuberculosis (Mtb) and in particular those that relate to its survival, adaptability and pathogenicity. Mtb is the causative agent of tuberculosis, an infectious disease that affects millions of people globally. Common anti-tuberculosis targets are focused on immobilizing a vital cysteine amino acid residue in enzymes that plays critical roles in redox and non-redox catalysis, the modulation of the protein, enzyme activity, protein structure and folding, metal coordination, and posttranslational modifications of newly synthesized proteins. This review examines five Mtb enzymes that contain an active site cysteine residue and are considered as key targets for anti-tuberculosis drugs, namely alkyl hydroperoxide reductase (AhpC), dihydrolipoamide dehydrogenase (Lpd), aldehyde dehydrogenase (ALDH), methionine aminopeptidase (MetAP) and cytochromes P450. AhpC and Lpd protect Mtb against oxidative and nitrosative stress, whereas AhpC neutralizes peroxide/peroxynitrite substrates with two active site cysteine residues. Mtb ALDH detoxifies aldehydes, using a nucleophilic active site cysteine to form an oxyanion thiohemiacetal intermediate, whereas MtMetAP’s active site cysteine is essential for substrate recognition. The P450s metabolize various endogenous and exogenous compounds. Targeting these critical active site cysteine residues could disrupt enzyme functions, presenting a promising avenue for developing anti-mycobacterial agents.

The rapidly evolving psychedelic industry has garnered considerable attention due to 3,4-methylenedioxymethamphetamine-assisted psychotherapy's ground-breaking success in treating moderate-to-severe Post-traumatic Stress Disorder in two Phase 3 clinical trials. This has opened Pandora's box for the development of innovative therapeutic modalities. Of particular interest are the phenethylamines and their ability to inhibit monoamine transporters. In this study, we employed the quantitative structure–activity relationship methodology to develop three vigorous models for the reuptake of serotonin, dopamine, and norepinephrine through monoamine transporters. These models were thoroughly validated using various criteria, including fitting (R2DAT = 0.869, R2SERT = 0.828, and R2NET = 0.887), internal (Q2looDAT = 0.795, Q2looSERT = 0.784, and Q2looNET = 0.820), and external (RMSEextDAT = 0.373, R2extDAT = 0.831, RMSEextSERT = 0.200, R2extSERT = 0.955, RMSEextNET = 0.318, and R2extNET = 0.711) criteria.

Spontaneous deamidation of amino acids is a physiologically important process, particularly for protein aging and diseases. Despite its widespread occurrence, the mechanism of glutamine deamidation particularly within proteins remains poorly understood. We have used a multiscale computational approach to investigate glutamine deamidation in the tripeptide Glycine-Glutamine-Glycine (Gly-Gln-Gly) and gamma S-Crystallin protein. Specifically, both the 5- and 6-membered water-assisted deamidation pathways in the tripeptide have been elucidated and compared. Both are found to occur in three stages: iminol formation, cyclization, and deamination. The rate-limiting step in each mechanism is nucleophilic attack of the backbone iminol nitrogen, formed in the first stage, at the glutamine's side-chain carbonyl carbon. For the 6- and 5-membered mechanisms, this occurs with a free energy cost of 136.4 and 179.5 kJ mol(-1), respectively. Thus, overall, in the Gly-Gln-Gly tripeptide, the 6-membered pathway is preferred. Furthermore, the free energies for forming cyclic intermediates and products at selected Gln residues (based on experimentally reported % deamidation) in gamma S-Crystallin have been obtained. It is found that the 5-membered product complex is exergonic at -25.3 kJ mol(-1), while the 6-membered product complex is calculated to be endergonic at 90.7 kJ mol(-1). Thus, the deamidation pathway in folded and constrained proteins may not exclusively follow the 6-membered route. Molecular dynamics (MD) simulations of gamma S-Crystallin indicate that deamidation is more likely to occur when two or more water molecules are in the proximity of the glutamine residue. Consequently, significant conformational changes are found to accompany Gln120 deamidation in gamma S-Crystallin. This in turn can influence water availability at the other Gln residues considered and hence potentially their deamidation. Collectively, these results provide comprehensive insights into spontaneous water-assisted deamidation of glutamine residues in peptides and into the role and impact of Gln deamidation in proteins.

Nonribosomal peptide synthetases (NRPSs) are important enzymes that synthesize an array of nongenetically encoded peptides. The latter have diverse physicochemical properties and roles. NRPSs are modular enzymes in which, for example, the condensation (C-) domain catalyzes the formation of amide bonds. The NRPS tyrocidine synthetase from Brevibacillus brevis is responsible for synthesizing the cyclic-peptide antibiotic tyrocidine. The first step is formation of an amide bond between a proline and phenylalanine which is catalyzed by a C-domain. In this study, a multiscale computational approach (molecular dynamics and QM/MM) has been used to investigate substrate binding and catalytic mechanism of the C-domain of tyrocidine synthetase. Overall, the mechanism is found to proceed through three exergonic steps in which an active site Histidine, His222, acts as a base and acid. First, His222 acts as a base to facilitate nucleophilic attack of the prolyl nitrogen at the phenylalanyl's carbonyl carbon. This is also the rate-limiting step with a free energy barrier of 38.8 kJ mol-1. The second step is collapse of the resulting tetrahedral intermediate with cleavage of the S-C bond between the phenylalanyl and its Ppant arm, along with formation of the above amide bond. Meanwhile, the now protonated His222 imidazole has rotated toward the newly formed thiolate of the Ppant arm. In the final step, His222 acts as an acid, protonating the thiolate and regenerating a neutral His222. The overall mechanism is found to be exergonic with the final product complex being 46.3 kJ mol-1 lower in energy than the initial reactant complex.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that remarkable facilitate the aminoacylation process during translation. With a high fidelity, the mischarged tRNA is prevented through implementing pre- and post-transfer proofreading mechanisms. For instance, Lysine-tRNA synthetase charges the native substrate, lysine, to its cognate tRNA. In spite of the great structural similarity between lysine to the noncognate and toxic ornithine, with the side chain of lysine being only one methylene group longer, LysRS is able to achieve this discrimination with a high efficiency. In this work, the hybrid quantum mechanics/molecular mechanics (QM/MM) investigation was applied to probe the pre-transfer editing mechanism catalyzed by lysyl-tRNA synthetase to reject the noncognte aminoacyl, L-ornityl (Orn), compared to the cognate substrate, L-lysyl. Particularly, the self-cyclization pre-transfer editing mechanism was explored for the two substrates. The substrate-assisted self-cyclization editing of Orn-AMP, where its phosphate moiety acts as the catalytic base, is found to be the rate-determining step with an energy barrier of 101.2 kJ mol-1. Meanwhile, the corresponding rate-limiting pathway for the native Lys-AMP lies at 140.2 kJ mol-1. This observation clearly indicated the infeasibility of this catalytic scenario in the presence of the native substrate. Interestingly, a thermodynamically favorable cyclic product of -92.9 kJ mol-1 with respect to the aminoacyl reactant complex demonstrated evidence of a successful pre-transfer editing. This reaction resulted in the discharge of the on-cognate -ornithine derivative from LysU's active site. These valuable mechanistic insights are valuable to enrich our knowledge of this extremely efficient and specific catalytic machinery of LysRS.Communicated by Ramaswamy H. Sarma

The enzyme malonamidase E2 catalytically hydrolyzes malonamate (MLA) into malonate and ammonia. Its active site contains an uncommon Ser– cisSer–Lys catalytic triad that is critical to its functioning. Mutations of the residues in this triad can not only provide insight into its key features but also potentially identify how it may be influenced or adapted, i.e., decreased or increased. In this study, the effects of single and double Ser/Cys exchanges on the wild-type Ser155– cisSer131–Lys62 catalytic triad (i.e., Cys155– cisSer131–Lys62 (S155C), Ser155– cisCys131–Lys62 (S131C), and Cys155– cisCys131–Lys62 (S131C/S155C)) were examined. In particular, the dynamics and stability of the resulting substituted triads were examined along with their inter-triad residue hydrogen bonding interactions as well as those with other nearby residues and the MLA substrate. The present results suggest that some mutations are more impactful than others. Indeed, mutation of cisSer131 to cisCys131 disrupts the triad and causes inconsistent hydrogen bonding interactions among the triad residues (i.e., Ser155, Cys131, and Lys62). In contrast, in the double mutant Cys155– cisCys131–Lys62, the triad's residues appear to exhibit greater conformation stability with more consistent hydrogen bond interactions, though not necessarily as in the wild type.

Due to the growing interest in directing aminoacyl-tRNA synthetases for antimicrobial therapies, evaluating the binding proficiency of potential inhibitors against this target holds significant importance. In this work, we proposed potential ligands that could properly bind to the crucial Zn(II) cofactor located in the active site of Threonyl-tRNA synthetases (ThrRS), potentially functioning as competitive inhibitors. Initially, detailed DFT quantum chemical study was conducted to examine the binding ability of threonine against unnatural amino acids to cofactor Zn(II). Then, the binding energy value for each suggested ligand has been determined and compared to the value determined for the native substrate, threonine. Our screening investigation showed that the native threonine should coordinate in a bidentate fashion to this Zn(II) which lead to the highest (binding energy) BE Thereby, the synthetic site of ThrRS rejects unnatural amino acids that cannot afford this type of coordination to Zn(II) ion which has been supported by our calculations. Moreover, based on their binding to the Zn(II) and the obtained BE values compared to the cognate threonine, many potent ligands have been suggested. Importantly, ligands with deprotonated warheads showed the highest binding ability amongst a list of potential hits. Further investigation on the selected ligands using molecular docking and QM/MM calculations confirmed our findings of the suggested ligands being able to bind efficiently in the active site of ThrRS. The suggested hits from this study should be valuable in paving routs for developing candidates as competitive inhibitors against the bacterial ThrRS.Communicated by Ramaswamy H. Sarma.

Molecular-level investigations of the Central Nervous System have been revolutionized by the development of computational methods, computing power, and capacity advances. These techniques have enabled researchers to analyze large amounts of data from various sources, including genomics, in vivo, and in vitro drug tests. In this review, we explore how computational methods and informatics have contributed to our understanding of mental health disorders and the development of novel drugs for neurological diseases, with a special focus on the emerging field of psychedelics. In addition, the use of state-of-the-art computational methods to predict the potential of drug compounds and bioinformatic tools to integrate disparate data sources to create predictive models is also discussed. Furthermore, the challenges associated with these methods, such as the need for large datasets and the diversity of in vitro data, are explored. Overall, this review highlights the immense potential of computational methods and informatics in Central Nervous System research and underscores the need for continued development and refinement of these techniques and more inclusion of Quantitative Structure-Activity Relationships (QSARs).

Cyclic peptides are known to have biologically important roles and may also be applicable to the pharmaceutical and other industries. Furthermore, thiols and amines, which are found throughout biological systems, can react to form S-N bonds and to date, ∼100 biomolecules containing such a bond have been identified. However, while there are in principle numerous S-N containing peptide-derived rings possible, only a few are presently known to occur in biochemical systems. Density functional theory-based calculations have been used to consider the formation and structure of S-N containing cyclic peptides from systematic series of linear peptides in which a cysteinyl has first been oxidized to a sulfenic or sulfonic acid. In addition, the possible effect of the cysteine's vicinal residue on the free energy of formation has also been considered. In general, when the cysteine is first oxidized to a sulfenic acid, only the formation of smaller S-N containing rings is calculated to be exergonic in aqueous solution. In contrast, when the cysteine is first oxidized to a sulfonic acid, the formation of all rings considered (with one exception) is calculated to be endergonic in aqueous solution. The nature of vicinal residue can influence ring formation through stabilizing or destabilizing intramolecular interactions.

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental syndromes diagnostically characterized by deficits in social communication and social interaction and repetitive, inflexible patterns of behaviors, interests, and thoughts. ASD affects people worldwide, irrespective of race, ethnicity, or socio-economic status, with debilitating effects on employment and interpersonal relationships. Though the atypical antipsychotics aripiprazole and risperidone are approved to treat irritability associated with ASD, these drugs may elicit treatment-limiting adverse effects, such as suicidal ideation, sedation, diarrhea, loss of appetite, dizziness, and weight gain. However, there are no approved pharmacotherapeutics for global symptoms of ASD, and better treatments are needed. Drugs with pro-social effects, such as 3,4-methylenedioxymethamphetamine (MDMA) and its analogues, may be beneficial here, as social anxiety and social avoidance are major complications of ASD that adversely impact the quality of life for sufferers and caregivers. This review describes the complex pharmacology of methylenedioxy amphetamine analogues (hereafter referred to as MDXX drugs), focusing on MDMA and 3,4-methylenedioxy-N-methyl-α-ethylphenylethylamine (MBDB) and how they may help treat ASD. Specifically, we address the roles of various drug-binding sites, metabolic enzymes, and chemical structure-activity relationships that mediate these substances' pharmacological and toxicological effects. Throughout the review, we emphasize the distinct profiles of individual stereoisomers of the MDXX drugs and how combining these enantiomers as racemic mixtures may explain the complexity of drug effects on behavior and physiology. We propose that the MDXX drugs represent a fruitful chemical space for developing clinically effective and relatively safer molecules and formulations for treating ASD.

The shikimate pathway, which produces aromatic amino acids and key intermediates, is critical to the viability of the tuberculosis-causing pathogen Mycobacterium tuberculosis. The enzyme 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAHPS) catalyzes the first committed step of this pathway and possesses regulatory functions. Its active site contains two cysteinyls: one (Cys87) bound to a metal ion, while the other (Cys440) is in proximity to the first but is located on a connecting loop. This arrangement seemingly appeared as a disulfide linkage. However, Cys440 is not metal binding, and its positioning indicates that it could collapse the disulfide linkage. Hence, its potential role may be more than simply structural support of the active site fold. Using a multiscale computational approach, molecular dynamics (MD) simulations, and DFT-based calculations, the influence of Cys440 on the active site properties has been investigated. MD simulations reveal an unusually long disulfide bond, more than 3.0 Å, whereas DFT calculations identified two stable active site conformers in the triplet and quintet spin states. Analysis of group spin density distribution identified antiferromagnetic coupling in each conformer, which suggests their relatively low potential energy and stable conformations. The conformer in the triplet spin state could favor enzyme reactivity due to its low HOMO-LUMO energy gap. In addition, reduction of the Cys440 thiolate group results in collapse of the active site metal-ligand configuration with large exothermicity. Hence, Cys440 could activate and inactivate the enzyme. For the first time, the study revealed the role of Cys440 as being vital for the catalytic activity of the enzyme rather than solely for the structural stabilization of its active site. Thus, the findings may lead to a novel basis for antituberculosis drug design and development that would disrupt the contributions of the Cys440.

Aminoacyl-tRNA synthetases (aaRS) are key enzymes in protein biosynthesis that employ various editing mechanisms to ensure faithful translation of genetic information. Seryl-tRNA synthetase (SerRS) and isoleucine-tRNA synthetase (IleRS) utilize pre-transfer editing mechanisms to prevent the incorporation of the undesired misactivated amino acids. In this study, molecular dynamics (MD) and quantum mechanics/QM (QM/semiempirical) were used to provide atomistic details regarding the pre-transfer editing against the non-cognates homocysteine (Hcy) by IleRS as well as cysteine (Cys) and threonine (Thr) by SerRS. Notably, in both enzymes, the mechanism is found to follow a stepwise self-cyclization substrate-assisted mechanism. Initially, dihedral scan around the substrate’s C β __ C γ bond takes place followed by a concerted step of R-S(O)H deprotonation concomitant with a nucleophilic attack. The rate limiting step to edit against Hcy by IleRS is the dihedral scan step and require 24.3 kcal/mol to proceed. Meanwhile, the rate-limiting step for editing against both Cys and Thr by SerRS is found to be the second step with Gibbs energy barriers of 20.4 and 26.6 kcal/mol, respectively. Interestingly, following the same pre-transfer editing pathway against the cognate Ser by SerRS results in a significantly higher energy barrier of 31.4 kcal/mol and energetically less favoured product complex lies at 17.7 kcal/mol. This finding clearly indicates an enzymatically infeasible process against Ser-AMP from kinetic and thermodynamic perspectives. The provided mechanistic insights should provide novel foundation required for the development of effective therapeutic agents for the treatment of the many disease states associated with these enzymes.

β-Hydroxynorvaline (βHNV) is unnatural amino acid structurally identical to the threonine amino acid with branched ethyl group instead of threonine's methyl. It is a known competitive inhibitor that readily bind to Threonyl-tRNA synthetase's (ThrRS) catalytic site and blocks its function. In this work, we utilized a combination of Molecular Dynamics simulation (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) methodologies to provide mechanistic insights into its inhibition reaction for ThrRS. Due to the presence of Zn(II) with its Lewis acidity character, only the ionized form of βHNV gives an enzymatically feasible energy barrier. Furthermore, in consistence with the homochirality behavior of this active site, we observed only one conformation of βHNV that could be acylated in the active site of ThrRS. Considering these new findings together with the recent search for new antibacterial agents, our findings should guide pharmaceutical scientists with further knowledge regarding the chemical nature of this drug. Moreover, benchmarking analysis of the utilized DFT functional has also been performed to identify the impact of various DFT functionals on representing the geometry and kinetics of our system. Notably, our Zn(II) containing chemical models are found to be responsive to the %HF contribution included together with the dispersion correction. Importantly, the BP86(0%HF)-D3 functional is found to display the greatest impact on the rate-limiting step kinetically. The crucial role played by Zn(II) is further enriched when its mutation with the chemically similar Cd(II) led to dramatic difference via obtaining less feasible reaction mechanism from thermodynamic and kinetic perspectives.

Collagen IV networks are an essential component of basement membranes that are important for their structural integrity and thus that of an organism's tissues. Improper functioning of these networks has been associated with several diseases. Cross-links, such as sulfilimine bonds interconnecting NC1 domains, are critical for forming and mechanically stabilizing these collagen IV networks. More specifically, the sulfilimine cross-links form between methionine (Met93) and lysine/hydroxylsine (Lys211/Hyl211) residues of NC1 domains. Therefore, the dynamic nature of the sulfilimine bond in collagen IV is crucial for network formation. To understand the dynamic nature of a neutral and protonated sulfilimine bond in collagen IV, we performed molecular dynamics (MD) simulations on four sulfilimine cross-linked systems (i.e., Met93S-NLys211, Met93S-NHLys211+, Met93S-NHyl211, and Met93S-NHHyl211+) of collagen IV. The MD results showed that the neutral Met93S-NLys211 system has the smallest protein backbone and showed the cross-linked residues' RMSD value. The conformational change analyses showed that the conformations of the sulfilimine cross-linked residues take on a U-shape for the Met93S-NHyl211 and Met93S-HNHyl211+ systems, whereas the conformations of the sulfilimine cross-linked residues are more open for the Met93S-NLys211, and Met93S-NHLys211+ systems. Protonation is a crucial biochemical process to stabilize the protein structure or the biological cross-links. Furthermore, the protonation of the sulfilimine bond could potentially influence hydrogen bond interaction with near amino acid residues, and according to water distribution analyses, the sulfilimine bond can potentially exist in one or more protonation states.

Human serum paraoxonase-1 (PON1) is an important hydrolase-type enzyme found in numerous tissues. Notably, it can exist in two isozyme-forms, Q and R, that exhibit different activities. This study presents an in silico (QSAR, Docking, MD and QM/MM) study of a set of compounds on the activity towards the PON1 isoenzymes (QPON1 and RPON1). Different rates of reaction for the Q and R isoenzymes were analyzed by modelling the effect of Q192R mutation on active sites. It was concluded that the Q192R mutation is not even close to the active site, while it is still changing the geometry of it. Using the combined genetic algorithm with multiple linear regression (GA-MLR) technique, several QSAR models were developed and relative activity rates of the isozymes of PON1 explained. From these, two QSAR models were selected, one each for the QPON1 and RPON1. Best selected models are four-variable MLR models for both Q and R isozymes with squared correlation coefficient R2 values of 0.87 and 0.83, respectively. In addition, the applicability domain of the models was analyzed based on the Williams plot. The results were discussed in the light of the main factors that influence the hydrolysis activity of the PON1 isozymes.

Cysteinyl-tRNA synthetase (CysRS) catalyzes the aminoacylation reaction of cysteine to its cognate tRNACys in the first step of protein translation. It is found that CysRS is different from other aaRSs as it transfers cysteine without the need for an editing reaction, which is not applicable in the case of serine despite the similarity in their structures. Surprisingly, the reasons why CysRS has high amino acid specificity are not clear yet. In this research, the binding configurations of Cys-AMP and its near-cognate amino acid Ser-AMP with CysRS are compared by Molecular Dynamics (MD). The results reveal that CysRS screens the substrate Cys-AMP to a certain extent in the process of combination and recognition, thus providing a guarantee for the high selectivity of the next reaction. While Ser-AMP is in a folded state in CysRS. In the meanwhile, the interaction between Cys-AMP and Zn963 in CysRS is much stronger than Ser-AMP. The substrate-assisted aminoacylation mechanism in CysRS is also explored by Quantum Mechanics/Molecular Mechanics (QM/MM) modeling. According to the QM/MM potential energies, the energy barrier of TSCys-AMP is 91.75 kJ/mol, while that of TSSer-AMP is close to 150 kJ/mol. Based on thermochemistry calculations, it is found that the product of Cys-AMP is more stable than the reactant. In contrast, Ser-AMP has a reactant that is more stable than its product. As a result, it reflects that the specificity of CysRS originates from both the kinetic and thermodynamical perspectives of the reaction. Our investigations demonstrate comprehensively on how CysRS recognizes and catalyzes the substrate Cys-AMP, hoping to provide some guidance for researchers in this area.

Microplastic (MP) pollution is a global challenge that requires immediate mitigation practices. Monitoring is crucial for quantifying MPs, but their mitigation remains very challenging due to several factors, including the lack of selective materials to specific polymers, and the low sensitivity of the current detection techniques. In this work, we introduce a novel design for the selective detection of MPs through fluorescence spectroscopy by exploiting conjugated polymer nanoparticles (CPNs). Fluorescent diketopyrrolopyrrole nanoparticles were prepared by nanoprecipi-tation to incorporate peripheral hyaluronic acid to increase their affinity for various plastics. The affinity of the new ligand for various types of MPs was examined through several character-ization techniques, including fluorescence spectroscopy and microscopy, nanoparticle tracking analysis and computational studies. The new CPN were shown to be highly fluorescent in the presence of typically abundant MPs, achieving very strong binding constants in the picomolar range. This very strong affinity for a broad family of plastics was found to be the results of cooperative supramolecular effects and topographical affinity, as probed by advanced microscopy and in silico studies. Furthermore, the new affinity probes were shown to be highly selective for MPs, allowing for their detection in heterogeneous samples, including soil debris and other organic contaminants. The new materials design introduced in this work constitute a promising platform for the development of novel MP detection devices directly useable at the point of collection. Moreover, it opens new avenue for the mitigation of this environmental hazard through tailorable materials.

Collagen IV is essential component of basement membrane in the tissues. It provides proper cellular structure by the formation of sulfilimine bond (S[double bond, length as m-dash]N) between methionine and lysine or hydroxylysine (cross-links) residues which can be formed with or without post-translational modification. The sulfilimine bond has critical roles in tissue development and human diseases. Peroxidasin, a basement membrane peroxidase, generates reactive halogen species including hypobromous (HOBr) acid and hypochlorous (HOCl) acid which help to form halosulfonium or haloamine. The sulfilamine bond can be formed either by the formation of halosulfonium or by the formation of halomine. The aim of the study is the investigation of the formation of sulfilimine bond and its nature in collagen IV using multi-scale approach that included MD, QM-cluster, systematic series of small models, and NBO analysis. These results suggest that sulfilimine bond can be formed either via brominated/chlorinated halosulfonium or haloamine pathway. The results of systematic series of small model indicate that the formation of sulfilimine complex from halosulfonium happens through the formation of positively charged halosulfonated sulfilimine complex. It also suggests that the formation of sulfilimine complex from haloamine occurs through the formation of positively charged sulfilimine complex where the S and N bond forms and halogen goes off at the same time. Furthermore, the NBO analysis suggest the S and N bond is strongly polarized toward nitrogen in both single protonated and neutral system, N δ- ← S δ+ and also indicate the existence of a coordinate covalent (i.e. dative) bond.

Soybean peroxidase effectively transformed selected amino- and hydroxyl-azoles by radical coupling to dimers and trimers, showing feasibility for wastewater treatment.

In this review, we delve into the topic of the pulmonary surfactant (PS) system, which is present in the respiratory system. The total composition of the PS has been presented and explored, from the types of cells involved in its synthesis and secretion, down to the specific building blocks used, such as the various lipid and protein components. The lipid and protein composition varies across species and between individuals, but ultimately produces a PS monolayer with the same role. As such, the composition has been investigated for the ways in which it imposes function and confers peculiar biophysical characteristics to the system as a whole. Moreover, a couple of theories/models that are associated with the functions of PS have been addressed. Finally, molecular dynamic (MD) simulations of pulmonary surfactant have been emphasized to not only showcase various group’s findings, but also to demonstrate the validity and importance that MD simulations can have in future research exploring the PS monolayer system.