Hyaluronan (HA) is a natural linear polysaccharide composed of disaccharide repeating units. HA is widely used in cosmetics and skin care product due to its excellent moisturizing ability. Recently, a novel derivative of hyaluronan, named Hya-HEAL+, has been synthesized and shown to have great ability in anti-aging skin care product applications. The novel derivative of hyaluronan (Hya-HEAL+) is modified with histidine side chain and hydrophobic group with a 30% to 50% degree of substitution of repeating units. Experimental results have shown that the novel derivative of hyaluronan (Hya-HEAL+) can effectively inhibit MMP-1, 3, 2, 9 (matrix metalloproteinase) which are enzymes that degrade collagen. By inhibiting the activity of MMP, the Hya-HEAL+ prevents the decomposition of collagen and shows an anti-aging effect. However, the molecular mechanisms of the inhabitation of MMP are still not clear. In this study, we investigate the molecular structure of Hya-HEAL+ and the molecular mechanisms of the inhibitory effect of Hya-HEAL+ on MMP through a full atomistic simulation approach. From nano-scale, we find that the hydrophobic group on Hya-HEAL+ is responsible for the structural difference between HA and Hya-HEAL+. Hya-HEAL+ interacts with MMP through hydrogen bonds, hydrophobic group and chelation of the active site zinc. The hydrophobic group increases the binding ability. Hya-HEAL+ binds to MMP and effectively prevents collagen degradation to achieve an anti-aging effect. This study provides fundamental insights into the conformations of Hya-HEAL+ and the binding pose of Hya-HEAL+ to MMP and help explaining the molecular properties and molecular mechanisms of the inhibitory effect of Hya-HEAL+ on MMP.