Specific carbohydrate-protein interactions are crucial in numerous physiological processes, disruption of which has been implicated in many different diseases like cancer. This provides researchers an opportunity to utilize carbohydrates as biomarkers and targets for therapeutics for such diseases. There has been a tremendous surge in the research being conducted towards the development of techniques to analyze carbohydrates and their specificity and affinity for different proteins. However, owing to their complex three-dimensional structure, stereochemistry, low binding affinities and broad specificity, carbohydrates have proven to be challenging to study. Therefore, new techniques and improvements in the existing methodologies are required. Here, we show that the incorporation of experimental data into molecular modeling can be used as a powerful combination to gain an understanding of the structural features of proteins and carbohydrates leading to the specificity in their interactions. Firstly, hydroxyl radical protein footprinting (HRPF) was used to establish a relationship between the oxidation of amino acids exposed on the surface of a protein and their solvent accessible surface area (SASA). Oxidation, as well as SASA, are both directly proportional to the exposure of an amino acid to the solvent. This relationship was used to estimate SASA of residues of a protein in solution, which was then successfully utilized as a score to quantify the quality of models generated through a molecular dynamics (MD) simulation and homology modeling. This relationship can also be used to study protein- carbohydrate interactions, which remains to be tested. Secondly, the functional groups of a monosaccharide essential for forming protein-carbohydrate interactions were identified by using co-crystal structures and per-atom binding energy analysis, which shows that not all chemically-equivalent functional groups are equally significant for binding. Lastly, the 3D structure of a group of monosaccharides was analyzed and it was observed that two monosaccharides can possess structural similarities depending on their alignment, which can be used to explain cross-reactivity between a protein and more than one carbohydrate.