Parkinson's disease is a widespread age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the midbrain along with the appearance of protein aggregates, termed as "Lewy bodies" in the surviving neuronal cells. The components of Lewy bodies include proteins such as α-synuclein, 14−3−3, Parkin, and LRRK2, along with other cellular organelles, which, in their native state, perform a plethora of vital biological functions within the human biome. Formation of these aggregates renders these components inactive, thereby interfering with homeostasis. In this regard, the current study attempts to investigate the complexation behavior of all human-based 14−3−3 isoforms with α-synuclein via a combination of classical and enhanced sampling techniques and thereby determine the causality of these protein−protein interactions. The study indicated that upon complexation, the aggregation propensity of both 14−3−3 and α-synuclein increases, and this increment is propelled by the interfacial residues on either protein. Furthermore, mutagenesis studies revealed that Lys214 of 14−3−3 (henceforth termed K214A) is crucial for the formation of this binary complex. Principal component analysis combined with clustering studies unveiled the stability of these complexes in terms of their conformational distribution across the entire MD trajectory. For K214A, these clustered states were sparsely located, thereby making the transitions between them slightly difficult. Dynamic cross-correlation maps (DCCM) revealed the role of residues in the range 80−130 of 14−3−3 having a potential allosteric role in driving this complexation process. Finally, a novel peptide-based supramolecular inhibitor was designed, which exhibited higher proficiency in limiting the 14−3−3/α-synuclein interaction compared to the previous inhibitor model. It was also revealed that the presence of this inhibitor induces structural rigidity in α-synuclein, making changes in its conformations extremely difficult, as observed through Umbrella Sampling studies. Based on available information, the current study provides an insight into the molecular-level understanding of protein−protein interactions underlying Parkinson's disease and adds on to the methods of devising novel therapeutic approaches to treat the same.