QM/MM Modeling Aided Enzyme Engineering in Natural Products Biosynthesis.

Natural products and their derivatives are widely used across various industries, particularly pharmaceuticals. Modern engineered biosynthesis provides an alternative way of producing and meeting the growing need for diverse natural products. Natural enzymes, on the other hand, often exhibit unsatisfactory catalytic characteristics and necessitate further enzyme engineering modifications. QM/MM, as a powerful and extensively used computational tool in the field of enzyme catalysis, has been increasingly applied in rational enzyme engineering over the past decade. In this review, we summarize recent advances in QM/MM computational investigation on enzyme catalysis and enzyme engineering for natural product biosynthesis. The challenges and perspectives for future QM/MM applications aided enzyme engineering in natural product biosynthesis will also be discussed.