School of Biochemistry , University of Bristol , University Walk, Bristol BS8 1TD , United Kingdom.
Centre for Computational Chemistry, School of Chemistry , University of Bristol , Cantock's Close, Bristol BS8 1TS , United Kingdom.
J Chem Inf Model. 2019 Aug 26;59(8):3365-3369. doi: 10.1021/acs.jcim.9b00442. Epub 2019 Aug 7.
Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take less than 24 CPU hours, a greater than 99% reduction, and do not require fitting against experimental data or significant parametrization. This computational assay also reveals mechanistic details of β-lactam breakdown and should assist in evaluating emerging β-lactamase variants and developing new antibiotics.
A 类 β-内酰胺酶导致对 β-内酰胺类抗生素的临床相关耐药性。碳青霉烯类物质的降解是一个特别令人关注的问题。我们提出了一种有效的量子力学/分子力学（QM/MM）分子模拟方案，该方案能够准确预测β-内酰胺酶对碳青霉烯类物质的活性。模拟时间不到 24 个 CPU 小时，减少了 99%以上，并且不需要针对实验数据进行拟合或进行大量参数化。这种计算测定方法还揭示了β-内酰胺类物质分解的机制细节，应该有助于评估新出现的β-内酰胺酶变体和开发新的抗生素。
